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OMIM | SHORT STATURE HOMEOBOX, Y-LINKED; SHOXY | | Leri-Weill dyschondrosteosis | Autosomal dominant | Y | See short stature homeobox (SHOX; {312865}) for a discussion of the SHOXY gene, which is located in the pseudoautosomal region. | PMID:9140395,PMID:9259282 |
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OMIM | SHORT STATURE HOMEOBOX, Y-LINKED; SHOXY | | Langer mesomelic dysplasia | Autosomal recessive | Y | See short stature homeobox (SHOX; {312865}) for a discussion of the SHOXY gene, which is located in the pseudoautosomal region. | PMID:9140395,PMID:9259282 |
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OMIM | SHORT STATURE HOMEOBOX, Y-LINKED; SHOXY | | Short stature, idiopathic familial | | Y | See short stature homeobox (SHOX; {312865}) for a discussion of the SHOXY gene, which is located in the pseudoautosomal region. | PMID:9140395,PMID:9259282 |
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OMIM | SEX-DETERMINING REGION Y; SRY | TESTIS-DETERMINING FACTOR; TDF;;
TESTIS-DETERMINING FACTOR ON Y; TDY, SRY, TDF, TDY, SRXX1, SRXY1 | 46XY sex reversal 1 | | Y | {26:Goodfellow and Lovell-Badge (1993)} provided a major review of SRY and sex determination in mammals.
From the study of normal males and females, persons with abnormal numbers of sex chromosomes, and persons carrying variant Y chromosomes, a factor (or factors) that determines the differentiation of the indifferent gonads into testes is known to be located on the Y chromosome and specifically on the short arm; this was designated testis-determining factor (TDF) in the 1960s. (See Mendelian Inheritance in Man, 4th ed., fig. 1, p. lix, 1975.)
{53:Mittwoch (1992)} argued that the 'dogma' that all differences distinguishing male and female mammals can be traced to the presence or absence of a single gene encoding a testis-determining factor lacks, as she said, 'biological validity.' She suggested that the genotype of the functional, i.e., fertile, male differs from that of a functional female by the presence of multiple Y-chromosomal genes in association with but a single X chromosome.|* {46:Lahr et al. (1995)} used RT-PCR to investigate the transcription of the Sry gene in mice. The gene was transcribed in the hypothalamus, midbrain, and testis of adult male but not adult female mice. Whereas the transcripts in the adult testis were circular, those in brain were linear and therefore capable of translation. {46:Lahr et al. (1995)} hypothesized that some male specific properties of the brain may be generated directly by the SRY gene product.
With use of reporter plasmids, gel shift assays, and transfection experiments, {35:Hossain and Saunders (2001)} determined that the product of the WT1 gene ({607102}) transactivates SRY by binding to its promoter region. They also found that WT1 carrying any of 4 common mutations causing Denys-Drash syndrome failed to activate the SRY promoter.
{48:Li et al. (2001)} found that the R133W SRY mutation ({607102.0019}), which lies within the HMG DNA-binding domain, had little or no effect on specific DNA binding and bending assays, but resulted in a significant change in cellular location of SRY upon transfection into COS-7 cells and into a male rat gonadal ridge embryogenic cell line. In both model cell systems, wildtype SRY localized to the nuclear compartment, whereas the mutant SRY showed a broad distribution in the cytoplasm and nucleus similar to that observed with deletion of the C-terminal nuclear localization signal (NLS).
{61:Sekido and Lovell-Badge (2008)} demonstrated that Sry binds to multiple elements within a Sox9 ({608160}) gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with steroidogenic factor-1 (SF1) an orphan nuclear receptor encoded by the gene Nr5a1 ({184757}). Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. {61:Sekido and Lovell-Badge (2008)} concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and the failure of these mechanisms in cases of sex reversal.
{28:Hansen et al. (2013)} found that the mouse Sry circular RNA contains 16 putative microRNA-138 (MIR138; see {613394})-binding sites. They showed that Sry bound Mir138 and functioned as an Mir138 sponge, reducing the ability of Mir138 to downregulate expression of a reporter gene.
{45:Kuroki et al. (2013)} found that Jmjd1a ({611512}) regulates expression of the mammalian Y chromosome Sry. Jmjd1a directly and positively controls Sry expression by regulating H3K9me2 marks. {45:Kuroki et al. (2013)} found that Jmjd1a-null mice that were XY were frequently sex reversed, either partially, with a testis and an ovary (12 of 58 animals), or completely, with 2 ovaries (34 of 58 animals). In contrast, all Jmjd1a wildtype and heterozygous XY mice had 2 testes. {45:Kuroki et al. (2013)} concluded that their studies revealed a pivotal role of histone demethylation in mammalian sex determination.|* {64:Sinclair et al. (1990)} identified a gene, which they named SRY (sex-determining region Y), within a 35-kb sex-determining region on the human Y chromosome that was adjacent to the pseudoautosomal boundary. The mouse homolog Sry was subsequently cloned and found to be present in Sxr-prime mice, which have the smallest part of the Y chromosome known to be sex-determining ({27:Gubbay et al., 1990}). Furthermore, Sry was deleted from a mutant Y chromosome that was no longer sex-determining ({27:Gubbay et al., 1990}).
{65:Su and Lau (1993)} found that the SRY open reading frame encodes a deduced 204-amino acid protein with a calculated molecular mass of 24 kD. There is a DNA-binding HMG motif in the middle of the protein.
{11:Capel et al. (1993)} found that a circular Sry transcript consisting of a single exon represented more than 90% of Sry transcripts in adult mouse testis. In contrast, developing mouse genital ridge exclusively expressed linear Sry transcripts. Circular Sry transcripts were not detected in any other mouse tissue examined and were most likely noncoding. {11:Capel et al. (1993)} noted that the human SRY gene is transcribed into a linear form only and lacks the flanking inverted repeats required for circular splicing.|* {65:Su and Lau (1993)} determined that SRY is an intronless gene that spans 3.8 kb. Analysis of the proximal flanking region revealed 2 GC-rich regions containing several Sp1 ({189906})-binding sites. The gene also contains a TATAAA motif for the binding of TFIID (TAF5; {601787}) and a kappa B enhancer element for the binding of NF-kappa-B (see {164011}).|* DNA-binding proteins are typically involved in the developmental control of gene expression. High mobility group (HMG) proteins contain a DNA-binding motif called the HMG domain. They have been proposed to act either as target-specific transcription factors or as chromatin structure regulatory elements, or both. {40:Jay et al. (1997)} stated that more than 100 HMG-box containing proteins have been reported and classified into 2 distinct subgroups according to the sequence specificity of the DNA binding, the number of HMG DNA-binding domains, and phylogenetic considerations. The first subgroup comprises proteins that are all potential transcription factors believed to control gene expression during development. They contain only 1 DNA-binding domain and they bind to DNA in a sequence-specific fashion. The second subgroup consists of all other HMG box-containing proteins, most of which contain more than 1 DNA-binding domain and can bind to DNA in a non-sequence-specific manner. SRY belongs to the first subgroup. Its cloning led to the discovery of a family of both autosomal and X-linked genes called SOX (for 'SRY-box' related) because of the strong homology of their DNA-binding domain with the HMG box of SRY.
{56:Page et al. (1987)} cloned part or all of what they thought to be the TDF gene, found that some sequences were highly conserved in mammals and even birds, and showed that the nucleotide sequence of the conserved DNA codes for zinc finger domains. ZFY (zinc finger protein, Y-linked; {314980}) was the designation approved by the HGM workshop committee, with ZFX being the X-linked counterpart. ZFY proved, however, not to be TDF ({57:Palmer et al., 1989}).|* SRY encodes a transcription factor that is a member of the high mobility group (HMG)-box family of DNA binding proteins.|* 46,XY Complete Gonadal Dysgenesis
{38:Jager et al. (1990)} analyzed the SRY gene in 12 XY sex-reversed females ({400044}) and identified a de novo 4-bp deletion ({480000.0001}) in a conserved DNA-binding motif in 1 patient.
{34:Hawkins et al. (1992)} studied the SRY gene in 5 phenotypic females with complete gonadal dysgenesis and a 46,XY karyotype reported by {4:Berkovitz et al. (1991)}. They used single-strand conformation polymorphism assay and DNA sequencing to screen the open reading frame and identified mutations in 3 of the 5 patients. Like all the previously described SRY mutations, these mutations--2 point mutations ({480000.0006} and {480000.0007}) and a single-base deletion ({480000.0008})--altered the putative DNA-binding region of the SRY protein.
{32:Hawkins (1993)} performed a mutation analysis of the SRY gene in XY females. He noted that 11 mutations had been described at that time, and all were within the DNA-binding HMG-box region of the protein.
{9:Cameron and Sinclair (1997)} stated that 26 different mutations in the SRY gene have been found in individuals with a 46,XY karyotype. They cited reports stating that no polymorphisms had been described in SRY among 50 normal males. De novo mutations in the SRY HMG-box region almost always resulted in 46,XY unambiguous females with no testicular differentiation. They found 5 reports of familial 46,XY complete gonadal dysgenesis associated with mutations in the SRY HMG-box region. In 4 of these reports, the father carried the same SRY mutation as his 46,XY daughter. None of the mutations appeared to be polymorphisms. Explanations for the sex reversal associated with these familial SRY mutations included paternal gonadal mosaicism for the mutation (yet to be proven) and incomplete penetrance of the mutation. Support for a penetrance effect came from murine studies in which at least 3 autosomal recessive alleles were found to interact with Y-chromosome alleles, resulting in the genesis of XY ovaries and true hermaphrodites ({19:Eicher and Washburn, 1986}). {9:Cameron and Sinclair (1997)} noted that timing and expression of SRY are exquisitely regulated and probably must reach a threshold. Consequently, a given mutation in SRY against a particular genetic background might produce sufficient SRY expression to reach the threshold required; testis formation can then ensue, accounting for an unaffected father.
{69:Uehara et al. (2002)} found missense mutations in the SRY gene in 2 of 3 patients with the complete form of XY gonadal dysgenesis. Combined with the results of a previous study ({68:Uehara et al., 1999}) in which 2 of 3 complete-type patients showed SRY abnormalities, the incidence was estimated at 67%, which is higher than previously thought. A metaanalysis of patients with SRY abnormalities showed an incidence of 52.5% for gonadal tumor formation in patients with SRY abnormalities. {69:Uehara et al. (2002)} gave a useful tabulation of the SRY abnormalities that had been described.
{31:Harley et al. (2003)} examined the SRY gene from 4 XY females, each with a missense mutation of a conserved arginine in either 1 of the 2 NLSs of the SRY HMG box. In all cases, mutant SRY protein was partly localized to the cytoplasm, whereas wildtype SRY was strictly nuclear. Each NLS can independently direct nuclear transport of a carrier protein in vitro and in vivo, with mutations in either affecting the rate and extent of nuclear accumulation. The N-terminal NLS function is independent of the conventional NLS-binding importins and requires cytoplasmic transport factors, whereas the C-terminal NLS is recognized by importin-beta (KPNB1; {602738}). The SRY mutant R133W ({480000.0019}) showed reduced importin-beta binding as a direct consequence of the sex-reversing C-terminal NLS mutation. Of the 3 other N-terminal NLS mutants examined, 1 unexpectedly showed a marked reduction in importin-beta binding, whereas the other 2 showed normal importin-beta binding, suggesting defects in the importin-independent pathway. {31:Harley et al. (2003)} concluded that SRY normally requires the 2 distinct NLS-dependent nuclear import pathways to reach sufficient levels in the nucleus for sex determination. The study documented cases of human disease that were explained, at a molecular level, by the impaired ability of a protein to accumulate in the nucleus.
46,XY True Hermaphroditism
{7:Braun et al. (1993)} reported a 46,XY true hermaphrodite who had a mutation of SRY in gonadal DNA but not in leukocyte DNA, suggesting that the mutation was postzygotic. Because of this finding, {24:Fuqua et al. (1997)} attempted to determine whether postzygotic mutations of SRY might explain the numerous cases of gonadal dysgenesis in which no SRY mutation was detected in leukocyte DNA. They evaluated 16 subjects with 46,XY gonadal dysgenesis who had a normal SRY sequence in leukocyte DNA, 5 of them having 46,XY complete gonadal dysgenesis. They did not find mutations in gonadal DNA from any of 16 subjects and concluded that postzygotic mutations of SRY are a rare cause of 46,XY gonadal dysgenesis.
{50:Maier et al. (2003)} reported a 46,XY true hermaphrodite who had a mutation in the SRY gene ({480000.0014}). The father, his 3 brothers, and his first-born son carried the identical mutation without phenotypic effects. {50:Maier et al. (2003)} concluded that the mutated protein retained enough activity to allow normal development in some individuals.
46,XX Gonadal Dysgenesis, Complete or Partial
{51:Margarit et al. (2000)} studied a 46,XX true hermaphrodite and found that Yp-specific sequences, including the SRY gene, had been transferred to the long arm of one of the X chromosomes at the Xq28 level. The derivative X chromosome of the patient lacked q-telomeric sequences. The authors suggested that this was the first report of a Yp/Xq translocation. The coexistence of testicular and ovarian tissue in the patient may have arisen by differential inactivation of the Y-bearing X chromosome, in which Xq telomeric sequences were missing.
{63:Sharp et al. (2005)} studied causes of incomplete masculinization in 15 individuals with segments of Yp translocated onto Xp. Expression studies showed little evidence for the spreading of X inactivation into Yp chromatin; however, in several cases, disruption of gene expression occurred independently of X inactivation, suggesting position effects resulting from chromosomal rearrangement. In particular, 5 of 6 translocation carriers with an intersex phenotype had either translocation breakpoints very close to SRY, or disrupted expression of genes near SRY in a manner unrelated to X inactivation. Southern blot analysis suggested the presence of a cryptic rearrangement 3 to 8 kb proximal to SRY in 1 case. {63:Sharp et al. (2005)} suggested that incomplete masculinization in cases of X/Y translocation is a result of disruption of normal SRY expression by position effects rather than X inactivation.
{76:Zenteno et al. (1997)} described a Mexican family in which 2 brothers, aged 28 and 26, were thought to be instances of 'classic' XX males without genital ambiguity but were found to be negative for several Y-chromosome sequences, including SRY. The data suggested that an inherited loss-of-function mutation in a gene participating in the sex-determining cascade can induce normal male sexual differentiation in the absence of SRY.
Mosaicism
{62:Shahid et al. (2005)} performed molecular genetics studies in 3 Turner syndrome patients all presenting with 45,X/46,XY mosaic karyotype. Two patients carried mutations within the HMG box, and 1 patient carried a frameshift mutation downstream of the HMG box. The authors suggested that lack of a second sex chromosome in a majority of cells (mosaic karyotype and mutation in the SRY gene) in these patients may have triggered the short stature.
{47:Lange et al. (2009)} identified 60 unrelated individuals with isodicentric (idic) or isocentromeric (iso) Y chromosomes, 51 of which apparently arose via a palindromic mechanism, yielding an idicYp in 49 cases and an idicYq in 2 cases, whereas the remaining 9 arose via recombination in heterochromatic sequences, yielding an idicYp in 2 cases and an isoYp in 7 cases. As expected, the 2 individuals carrying the idicYq chromosomes lacked the SRY gene and were phenotypic females; however, 18 of the 58 idicYp and isoYp individuals, who had 2 copies of SRY, were also 'sex-reversed' and raised as females or found in childhood to have 1 degenerate ovary and 1 testis. {47:Lange et al. (2009)} observed that the average intercentromeric distance in the feminized individuals was twice that in the males (p less than 10(-6)), supporting the hypothesis that mitotic instability and resultant XO mosaicism may cause sex reversal.|* TDF was ultimately mapped to the human Y chromosome by molecular examination of sex-reversed patients. Analysis of 4 XX males with testes who had minute portions of the Y material translocated to the X chromosome was critical in defining the sex-determining region on the human Y chromosome ({57:Palmer et al., 1989}; {64:Sinclair et al., 1990}). The sex-determining region on the human Y chromosome was later defined to a 35-kb region of Y-specific DNA adjacent to the pseudoautosomal boundary ({64:Sinclair et al., 1990}).
{3:Behlke et al. (1993)} found that 2 RNAs hybridized to a 4,741-bp genomic segment of the sex-determining region of the human Y chromosome: one transcript deriving from SRY, and a second transcript cross-hybridizing to a pseudogene located 2.5 kb 5-prime of the SRY open reading frame. Analysis of the SRY transcript suggested that the entire SRY protein is encoded by a single exon.|* The human and mouse Sry genes share 89% amino acid identity in their HMG box domains, but they diverge significantly in their C termini. {14:Coward et al. (1994)} found that Sry alleles from all mouse strains examined encode a glutamine- and histidine-rich C-terminal domain. Sry alleles encoding a polyglutamine tract of either 13 or 11 glutamine residues were associated with partial (fetal) or complete sex reversal, respectively, when introduced on a C57BL/6J background. Alleles encoding a tract of 12 glutamine residues were not associated with sex reversal.
Only the HMG box region of the SRY gene has been conserved through evolution, suggesting that SRY function depends solely on the HMG box and therefore acts as an architectural transcription factor. In mice, SRY includes a large CAG trinucleotide repeat region encoding a C-terminal glutamine-rich domain that acts as a transcriptional trans-activator in vitro. The absence of this or any other potential trans-activating domain in other mammals, however, has raised doubts as to its biologic relevance. To test directly whether the glutamine-rich region is required for SRY function in vivo {6:Bowles et al. (1999)} created truncation mutations of the Mus musculus SRY gene and tested their ability to induce testis formation in XX embryos using a transgenic mouse assay. SRY constructs that encoded proteins lacking a glutamine-rich region were unable to effect male sex determination, in contrast to their wildtype counterparts. {6:Bowles et al. (1999)} concluded that the glutamine-rich repeat domain of the mouse SRY protein has an essential role in sex determination in vivo and that SRY may act via a fundamentally different biochemical mechanism in mice compared with other mammals.
{55:Nef et al. (2003)} demonstrated that the insulin receptor tyrosine kinase family, comprising INSR ({147670}), IGF1R ({147370}), and IRR ({147671}), is required for the appearance of male gonads and thus for male sexual differentiation in mice. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry and the early testis-specific marker Sox9 ({608160}) indicated that the insulin signaling pathway is required for male sex determination.
In 6 sterile heifers that were female in appearance and in genital organs, {42:Kawakura et al. (1996)} found that blood, skin, spleen, and kidney showed a normal male 60,XY karyotype. Although the SRY gene was detected by PCR in a normal bulls, it was not detected in normal cows or in 3 60,XY female bovine cases studied.|* Using a human SRY probe, {22:Foster et al. (1992)} identified and cloned related genes from the Y chromosome of 2 marsupial species. Comparisons of eutherian ('placental') and metatherian (marsupial) Y-located SRY sequences suggested rapid evolution of these genes, especially outside the region encoding the DNA-binding 'high mobility group' domain (HMG box). The SRY homolog and the homolog of the mouse Ube1y were the first genes to be identified on the marsupial Y chromosome. {74:Whitfield et al. (1993)} and {67:Tucker and Lundrigan (1993)} likewise found that whereas the central 'high mobility group' domain of about 78 amino acids of the SRY protein is highly conserved, evolution in primates and in mice and rats has been rapid in the regions flanking the conserved domain. The high degree of sequence divergence and the frequency of nonsynonymous mutations suggested either that the majority of the coding sequence has no functional significance and therefore is not functionally constrained or that it has been subject to directional selection with species-specific adaptive divergence.
{23:Foster and Graves (1994)} identified a sequence on the marsupial X chromosome that shares homology with SRY and shows near-identity with the mouse and human SOX3 gene ({313430}; formerly called a3), the SOX gene most closely related to SRY. {23:Foster and Graves (1994)} suggested that the highly conserved X chromosome-linked SOX3 represents the ancestral SOX gene from which the sex-determining SRY gene was derived.
In therian mammals (placentals and marsupials), sex is determined by an XX female:XY male system in which the SRY gene on the Y chromosome affects male determination. Birds have a ZW female:ZZ male system with no homology with mammalian sex chromosomes. In birds, dosage of a Z-borne gene, possibly DMRT1 ({602424}), affects male determination. Platypus employ a sex-determining system of 5 X and 5 Y chromosomes. Females have 2 copies of the 5 Xs; males have 5X and 5Y chromosomes, which form an alternating XY chain during male meiosis. {71:Veyrunes et al. (2008)} found no homology between the 10 platypus sex chromosomes and the ancestral therian X chromosome, which is homologous to platypus chromosome 6. Orthologs of genes in the conserved region of human X (including SOX3, the gene from which SRY evolved) all map to platypus chromosome 6, which therefore represents the ancestral autosome from which the therian X and Y pair derived. The platypus X chromosomes have substantial homology with the bird Z chromosome (including DMRT1), and to segments syntenic with this region in the human genome. {71:Veyrunes et al. (2008)} concluded that the therian X and Y chromosomes, including the SRY gene, evolved from an autosomal pair after the divergence of monotremes only 166 million years ago.
{36:Hughes et al. (2010)} finished sequencing the male-specific region of the Y chromosome (MSY) in chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. Comparison of the MSYs of the 2 species showed that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. {36:Hughes et al. (2010)} suggested that the extraordinary divergence of the chimpanzee and human MSYs was driven by 4 synergistic factors: the prominent role of the MSY in sperm production, 'genetic hitchhiking' effects in the absence of meiotic crossingover, frequent ectopic recombination within the MSY, and species differences in mating behavior. | PMID:10431249,PMID:10459352,PMID:10602113,PMID:10843173,PMID:10852465,PMID:11278460,PMID:11641389,PMID:12107262,PMID:12111377,PMID:12764225,PMID:12793612,PMID:1339396,PMID:1406969,PMID:1415266,PMID:14628051,PMID:1483689,PMID:15687343,PMID:1570829,PMID:15863672,PMID:1619028,PMID:1634224,PMID:1639410,PMID:1695712,PMID:1734522,PMID:18454134,PMID:18463302,PMID:1956279,PMID:19737515,PMID:20072128,PMID:2028253,PMID:2030730,PMID:2247149,PMID:2247150,PMID:2247151,PMID:23446346,PMID:2374589,PMID:24009392,PMID:2401216,PMID:2594087,PMID:3464001,PMID:3545061,PMID:3690661,PMID:3738510,PMID:4161595,PMID:572812,PMID:5951402,PMID:7017147,PMID:7684656,PMID:7717397,PMID:7718558,PMID:7774012,PMID:7985018,PMID:7987333,PMID:8012385,PMID:8105086,PMID:8111368,PMID:8122913,PMID:8127908,PMID:8159753,PMID:8244390,PMID:8257986,PMID:8353496,PMID:8355783,PMID:8355784,PMID:8434602,PMID:8447323,PMID:8774960,PMID:8978769,PMID:9024280,PMID:9143916,PMID:9150734,PMID:9215677,PMID:9341880,PMID:9443877,PMID:9450909,PMID:9521592 |
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OMIM | SEX-DETERMINING REGION Y; SRY | TESTIS-DETERMINING FACTOR; TDF;;
TESTIS-DETERMINING FACTOR ON Y; TDY, SRY, TDF, TDY, SRXX1, SRXY1 | 46XX sex reversal 1 | | Y | {26:Goodfellow and Lovell-Badge (1993)} provided a major review of SRY and sex determination in mammals.
From the study of normal males and females, persons with abnormal numbers of sex chromosomes, and persons carrying variant Y chromosomes, a factor (or factors) that determines the differentiation of the indifferent gonads into testes is known to be located on the Y chromosome and specifically on the short arm; this was designated testis-determining factor (TDF) in the 1960s. (See Mendelian Inheritance in Man, 4th ed., fig. 1, p. lix, 1975.)
{53:Mittwoch (1992)} argued that the 'dogma' that all differences distinguishing male and female mammals can be traced to the presence or absence of a single gene encoding a testis-determining factor lacks, as she said, 'biological validity.' She suggested that the genotype of the functional, i.e., fertile, male differs from that of a functional female by the presence of multiple Y-chromosomal genes in association with but a single X chromosome.|* {46:Lahr et al. (1995)} used RT-PCR to investigate the transcription of the Sry gene in mice. The gene was transcribed in the hypothalamus, midbrain, and testis of adult male but not adult female mice. Whereas the transcripts in the adult testis were circular, those in brain were linear and therefore capable of translation. {46:Lahr et al. (1995)} hypothesized that some male specific properties of the brain may be generated directly by the SRY gene product.
With use of reporter plasmids, gel shift assays, and transfection experiments, {35:Hossain and Saunders (2001)} determined that the product of the WT1 gene ({607102}) transactivates SRY by binding to its promoter region. They also found that WT1 carrying any of 4 common mutations causing Denys-Drash syndrome failed to activate the SRY promoter.
{48:Li et al. (2001)} found that the R133W SRY mutation ({607102.0019}), which lies within the HMG DNA-binding domain, had little or no effect on specific DNA binding and bending assays, but resulted in a significant change in cellular location of SRY upon transfection into COS-7 cells and into a male rat gonadal ridge embryogenic cell line. In both model cell systems, wildtype SRY localized to the nuclear compartment, whereas the mutant SRY showed a broad distribution in the cytoplasm and nucleus similar to that observed with deletion of the C-terminal nuclear localization signal (NLS).
{61:Sekido and Lovell-Badge (2008)} demonstrated that Sry binds to multiple elements within a Sox9 ({608160}) gonad-specific enhancer that they called TESCO (testis-specific enhancer of Sox9 core) in mice, and that it does so along with steroidogenic factor-1 (SF1) an orphan nuclear receptor encoded by the gene Nr5a1 ({184757}). Mutation, cotransfection, and sex-reversal studies all pointed to a feedforward, self-reinforcing pathway in which SF1 and SRY cooperatively upregulate SOX9; then, together with SF1, SOX9 also binds to the enhancer to help maintain its own expression after that of SRY has ceased. {61:Sekido and Lovell-Badge (2008)} concluded that their results permitted further characterization of the molecular mechanisms regulating sex determination, their evolution, and the failure of these mechanisms in cases of sex reversal.
{28:Hansen et al. (2013)} found that the mouse Sry circular RNA contains 16 putative microRNA-138 (MIR138; see {613394})-binding sites. They showed that Sry bound Mir138 and functioned as an Mir138 sponge, reducing the ability of Mir138 to downregulate expression of a reporter gene.
{45:Kuroki et al. (2013)} found that Jmjd1a ({611512}) regulates expression of the mammalian Y chromosome Sry. Jmjd1a directly and positively controls Sry expression by regulating H3K9me2 marks. {45:Kuroki et al. (2013)} found that Jmjd1a-null mice that were XY were frequently sex reversed, either partially, with a testis and an ovary (12 of 58 animals), or completely, with 2 ovaries (34 of 58 animals). In contrast, all Jmjd1a wildtype and heterozygous XY mice had 2 testes. {45:Kuroki et al. (2013)} concluded that their studies revealed a pivotal role of histone demethylation in mammalian sex determination.|* {64:Sinclair et al. (1990)} identified a gene, which they named SRY (sex-determining region Y), within a 35-kb sex-determining region on the human Y chromosome that was adjacent to the pseudoautosomal boundary. The mouse homolog Sry was subsequently cloned and found to be present in Sxr-prime mice, which have the smallest part of the Y chromosome known to be sex-determining ({27:Gubbay et al., 1990}). Furthermore, Sry was deleted from a mutant Y chromosome that was no longer sex-determining ({27:Gubbay et al., 1990}).
{65:Su and Lau (1993)} found that the SRY open reading frame encodes a deduced 204-amino acid protein with a calculated molecular mass of 24 kD. There is a DNA-binding HMG motif in the middle of the protein.
{11:Capel et al. (1993)} found that a circular Sry transcript consisting of a single exon represented more than 90% of Sry transcripts in adult mouse testis. In contrast, developing mouse genital ridge exclusively expressed linear Sry transcripts. Circular Sry transcripts were not detected in any other mouse tissue examined and were most likely noncoding. {11:Capel et al. (1993)} noted that the human SRY gene is transcribed into a linear form only and lacks the flanking inverted repeats required for circular splicing.|* {65:Su and Lau (1993)} determined that SRY is an intronless gene that spans 3.8 kb. Analysis of the proximal flanking region revealed 2 GC-rich regions containing several Sp1 ({189906})-binding sites. The gene also contains a TATAAA motif for the binding of TFIID (TAF5; {601787}) and a kappa B enhancer element for the binding of NF-kappa-B (see {164011}).|* DNA-binding proteins are typically involved in the developmental control of gene expression. High mobility group (HMG) proteins contain a DNA-binding motif called the HMG domain. They have been proposed to act either as target-specific transcription factors or as chromatin structure regulatory elements, or both. {40:Jay et al. (1997)} stated that more than 100 HMG-box containing proteins have been reported and classified into 2 distinct subgroups according to the sequence specificity of the DNA binding, the number of HMG DNA-binding domains, and phylogenetic considerations. The first subgroup comprises proteins that are all potential transcription factors believed to control gene expression during development. They contain only 1 DNA-binding domain and they bind to DNA in a sequence-specific fashion. The second subgroup consists of all other HMG box-containing proteins, most of which contain more than 1 DNA-binding domain and can bind to DNA in a non-sequence-specific manner. SRY belongs to the first subgroup. Its cloning led to the discovery of a family of both autosomal and X-linked genes called SOX (for 'SRY-box' related) because of the strong homology of their DNA-binding domain with the HMG box of SRY.
{56:Page et al. (1987)} cloned part or all of what they thought to be the TDF gene, found that some sequences were highly conserved in mammals and even birds, and showed that the nucleotide sequence of the conserved DNA codes for zinc finger domains. ZFY (zinc finger protein, Y-linked; {314980}) was the designation approved by the HGM workshop committee, with ZFX being the X-linked counterpart. ZFY proved, however, not to be TDF ({57:Palmer et al., 1989}).|* SRY encodes a transcription factor that is a member of the high mobility group (HMG)-box family of DNA binding proteins.|* 46,XY Complete Gonadal Dysgenesis
{38:Jager et al. (1990)} analyzed the SRY gene in 12 XY sex-reversed females ({400044}) and identified a de novo 4-bp deletion ({480000.0001}) in a conserved DNA-binding motif in 1 patient.
{34:Hawkins et al. (1992)} studied the SRY gene in 5 phenotypic females with complete gonadal dysgenesis and a 46,XY karyotype reported by {4:Berkovitz et al. (1991)}. They used single-strand conformation polymorphism assay and DNA sequencing to screen the open reading frame and identified mutations in 3 of the 5 patients. Like all the previously described SRY mutations, these mutations--2 point mutations ({480000.0006} and {480000.0007}) and a single-base deletion ({480000.0008})--altered the putative DNA-binding region of the SRY protein.
{32:Hawkins (1993)} performed a mutation analysis of the SRY gene in XY females. He noted that 11 mutations had been described at that time, and all were within the DNA-binding HMG-box region of the protein.
{9:Cameron and Sinclair (1997)} stated that 26 different mutations in the SRY gene have been found in individuals with a 46,XY karyotype. They cited reports stating that no polymorphisms had been described in SRY among 50 normal males. De novo mutations in the SRY HMG-box region almost always resulted in 46,XY unambiguous females with no testicular differentiation. They found 5 reports of familial 46,XY complete gonadal dysgenesis associated with mutations in the SRY HMG-box region. In 4 of these reports, the father carried the same SRY mutation as his 46,XY daughter. None of the mutations appeared to be polymorphisms. Explanations for the sex reversal associated with these familial SRY mutations included paternal gonadal mosaicism for the mutation (yet to be proven) and incomplete penetrance of the mutation. Support for a penetrance effect came from murine studies in which at least 3 autosomal recessive alleles were found to interact with Y-chromosome alleles, resulting in the genesis of XY ovaries and true hermaphrodites ({19:Eicher and Washburn, 1986}). {9:Cameron and Sinclair (1997)} noted that timing and expression of SRY are exquisitely regulated and probably must reach a threshold. Consequently, a given mutation in SRY against a particular genetic background might produce sufficient SRY expression to reach the threshold required; testis formation can then ensue, accounting for an unaffected father.
{69:Uehara et al. (2002)} found missense mutations in the SRY gene in 2 of 3 patients with the complete form of XY gonadal dysgenesis. Combined with the results of a previous study ({68:Uehara et al., 1999}) in which 2 of 3 complete-type patients showed SRY abnormalities, the incidence was estimated at 67%, which is higher than previously thought. A metaanalysis of patients with SRY abnormalities showed an incidence of 52.5% for gonadal tumor formation in patients with SRY abnormalities. {69:Uehara et al. (2002)} gave a useful tabulation of the SRY abnormalities that had been described.
{31:Harley et al. (2003)} examined the SRY gene from 4 XY females, each with a missense mutation of a conserved arginine in either 1 of the 2 NLSs of the SRY HMG box. In all cases, mutant SRY protein was partly localized to the cytoplasm, whereas wildtype SRY was strictly nuclear. Each NLS can independently direct nuclear transport of a carrier protein in vitro and in vivo, with mutations in either affecting the rate and extent of nuclear accumulation. The N-terminal NLS function is independent of the conventional NLS-binding importins and requires cytoplasmic transport factors, whereas the C-terminal NLS is recognized by importin-beta (KPNB1; {602738}). The SRY mutant R133W ({480000.0019}) showed reduced importin-beta binding as a direct consequence of the sex-reversing C-terminal NLS mutation. Of the 3 other N-terminal NLS mutants examined, 1 unexpectedly showed a marked reduction in importin-beta binding, whereas the other 2 showed normal importin-beta binding, suggesting defects in the importin-independent pathway. {31:Harley et al. (2003)} concluded that SRY normally requires the 2 distinct NLS-dependent nuclear import pathways to reach sufficient levels in the nucleus for sex determination. The study documented cases of human disease that were explained, at a molecular level, by the impaired ability of a protein to accumulate in the nucleus.
46,XY True Hermaphroditism
{7:Braun et al. (1993)} reported a 46,XY true hermaphrodite who had a mutation of SRY in gonadal DNA but not in leukocyte DNA, suggesting that the mutation was postzygotic. Because of this finding, {24:Fuqua et al. (1997)} attempted to determine whether postzygotic mutations of SRY might explain the numerous cases of gonadal dysgenesis in which no SRY mutation was detected in leukocyte DNA. They evaluated 16 subjects with 46,XY gonadal dysgenesis who had a normal SRY sequence in leukocyte DNA, 5 of them having 46,XY complete gonadal dysgenesis. They did not find mutations in gonadal DNA from any of 16 subjects and concluded that postzygotic mutations of SRY are a rare cause of 46,XY gonadal dysgenesis.
{50:Maier et al. (2003)} reported a 46,XY true hermaphrodite who had a mutation in the SRY gene ({480000.0014}). The father, his 3 brothers, and his first-born son carried the identical mutation without phenotypic effects. {50:Maier et al. (2003)} concluded that the mutated protein retained enough activity to allow normal development in some individuals.
46,XX Gonadal Dysgenesis, Complete or Partial
{51:Margarit et al. (2000)} studied a 46,XX true hermaphrodite and found that Yp-specific sequences, including the SRY gene, had been transferred to the long arm of one of the X chromosomes at the Xq28 level. The derivative X chromosome of the patient lacked q-telomeric sequences. The authors suggested that this was the first report of a Yp/Xq translocation. The coexistence of testicular and ovarian tissue in the patient may have arisen by differential inactivation of the Y-bearing X chromosome, in which Xq telomeric sequences were missing.
{63:Sharp et al. (2005)} studied causes of incomplete masculinization in 15 individuals with segments of Yp translocated onto Xp. Expression studies showed little evidence for the spreading of X inactivation into Yp chromatin; however, in several cases, disruption of gene expression occurred independently of X inactivation, suggesting position effects resulting from chromosomal rearrangement. In particular, 5 of 6 translocation carriers with an intersex phenotype had either translocation breakpoints very close to SRY, or disrupted expression of genes near SRY in a manner unrelated to X inactivation. Southern blot analysis suggested the presence of a cryptic rearrangement 3 to 8 kb proximal to SRY in 1 case. {63:Sharp et al. (2005)} suggested that incomplete masculinization in cases of X/Y translocation is a result of disruption of normal SRY expression by position effects rather than X inactivation.
{76:Zenteno et al. (1997)} described a Mexican family in which 2 brothers, aged 28 and 26, were thought to be instances of 'classic' XX males without genital ambiguity but were found to be negative for several Y-chromosome sequences, including SRY. The data suggested that an inherited loss-of-function mutation in a gene participating in the sex-determining cascade can induce normal male sexual differentiation in the absence of SRY.
Mosaicism
{62:Shahid et al. (2005)} performed molecular genetics studies in 3 Turner syndrome patients all presenting with 45,X/46,XY mosaic karyotype. Two patients carried mutations within the HMG box, and 1 patient carried a frameshift mutation downstream of the HMG box. The authors suggested that lack of a second sex chromosome in a majority of cells (mosaic karyotype and mutation in the SRY gene) in these patients may have triggered the short stature.
{47:Lange et al. (2009)} identified 60 unrelated individuals with isodicentric (idic) or isocentromeric (iso) Y chromosomes, 51 of which apparently arose via a palindromic mechanism, yielding an idicYp in 49 cases and an idicYq in 2 cases, whereas the remaining 9 arose via recombination in heterochromatic sequences, yielding an idicYp in 2 cases and an isoYp in 7 cases. As expected, the 2 individuals carrying the idicYq chromosomes lacked the SRY gene and were phenotypic females; however, 18 of the 58 idicYp and isoYp individuals, who had 2 copies of SRY, were also 'sex-reversed' and raised as females or found in childhood to have 1 degenerate ovary and 1 testis. {47:Lange et al. (2009)} observed that the average intercentromeric distance in the feminized individuals was twice that in the males (p less than 10(-6)), supporting the hypothesis that mitotic instability and resultant XO mosaicism may cause sex reversal.|* TDF was ultimately mapped to the human Y chromosome by molecular examination of sex-reversed patients. Analysis of 4 XX males with testes who had minute portions of the Y material translocated to the X chromosome was critical in defining the sex-determining region on the human Y chromosome ({57:Palmer et al., 1989}; {64:Sinclair et al., 1990}). The sex-determining region on the human Y chromosome was later defined to a 35-kb region of Y-specific DNA adjacent to the pseudoautosomal boundary ({64:Sinclair et al., 1990}).
{3:Behlke et al. (1993)} found that 2 RNAs hybridized to a 4,741-bp genomic segment of the sex-determining region of the human Y chromosome: one transcript deriving from SRY, and a second transcript cross-hybridizing to a pseudogene located 2.5 kb 5-prime of the SRY open reading frame. Analysis of the SRY transcript suggested that the entire SRY protein is encoded by a single exon.|* The human and mouse Sry genes share 89% amino acid identity in their HMG box domains, but they diverge significantly in their C termini. {14:Coward et al. (1994)} found that Sry alleles from all mouse strains examined encode a glutamine- and histidine-rich C-terminal domain. Sry alleles encoding a polyglutamine tract of either 13 or 11 glutamine residues were associated with partial (fetal) or complete sex reversal, respectively, when introduced on a C57BL/6J background. Alleles encoding a tract of 12 glutamine residues were not associated with sex reversal.
Only the HMG box region of the SRY gene has been conserved through evolution, suggesting that SRY function depends solely on the HMG box and therefore acts as an architectural transcription factor. In mice, SRY includes a large CAG trinucleotide repeat region encoding a C-terminal glutamine-rich domain that acts as a transcriptional trans-activator in vitro. The absence of this or any other potential trans-activating domain in other mammals, however, has raised doubts as to its biologic relevance. To test directly whether the glutamine-rich region is required for SRY function in vivo {6:Bowles et al. (1999)} created truncation mutations of the Mus musculus SRY gene and tested their ability to induce testis formation in XX embryos using a transgenic mouse assay. SRY constructs that encoded proteins lacking a glutamine-rich region were unable to effect male sex determination, in contrast to their wildtype counterparts. {6:Bowles et al. (1999)} concluded that the glutamine-rich repeat domain of the mouse SRY protein has an essential role in sex determination in vivo and that SRY may act via a fundamentally different biochemical mechanism in mice compared with other mammals.
{55:Nef et al. (2003)} demonstrated that the insulin receptor tyrosine kinase family, comprising INSR ({147670}), IGF1R ({147370}), and IRR ({147671}), is required for the appearance of male gonads and thus for male sexual differentiation in mice. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry and the early testis-specific marker Sox9 ({608160}) indicated that the insulin signaling pathway is required for male sex determination.
In 6 sterile heifers that were female in appearance and in genital organs, {42:Kawakura et al. (1996)} found that blood, skin, spleen, and kidney showed a normal male 60,XY karyotype. Although the SRY gene was detected by PCR in a normal bulls, it was not detected in normal cows or in 3 60,XY female bovine cases studied.|* Using a human SRY probe, {22:Foster et al. (1992)} identified and cloned related genes from the Y chromosome of 2 marsupial species. Comparisons of eutherian ('placental') and metatherian (marsupial) Y-located SRY sequences suggested rapid evolution of these genes, especially outside the region encoding the DNA-binding 'high mobility group' domain (HMG box). The SRY homolog and the homolog of the mouse Ube1y were the first genes to be identified on the marsupial Y chromosome. {74:Whitfield et al. (1993)} and {67:Tucker and Lundrigan (1993)} likewise found that whereas the central 'high mobility group' domain of about 78 amino acids of the SRY protein is highly conserved, evolution in primates and in mice and rats has been rapid in the regions flanking the conserved domain. The high degree of sequence divergence and the frequency of nonsynonymous mutations suggested either that the majority of the coding sequence has no functional significance and therefore is not functionally constrained or that it has been subject to directional selection with species-specific adaptive divergence.
{23:Foster and Graves (1994)} identified a sequence on the marsupial X chromosome that shares homology with SRY and shows near-identity with the mouse and human SOX3 gene ({313430}; formerly called a3), the SOX gene most closely related to SRY. {23:Foster and Graves (1994)} suggested that the highly conserved X chromosome-linked SOX3 represents the ancestral SOX gene from which the sex-determining SRY gene was derived.
In therian mammals (placentals and marsupials), sex is determined by an XX female:XY male system in which the SRY gene on the Y chromosome affects male determination. Birds have a ZW female:ZZ male system with no homology with mammalian sex chromosomes. In birds, dosage of a Z-borne gene, possibly DMRT1 ({602424}), affects male determination. Platypus employ a sex-determining system of 5 X and 5 Y chromosomes. Females have 2 copies of the 5 Xs; males have 5X and 5Y chromosomes, which form an alternating XY chain during male meiosis. {71:Veyrunes et al. (2008)} found no homology between the 10 platypus sex chromosomes and the ancestral therian X chromosome, which is homologous to platypus chromosome 6. Orthologs of genes in the conserved region of human X (including SOX3, the gene from which SRY evolved) all map to platypus chromosome 6, which therefore represents the ancestral autosome from which the therian X and Y pair derived. The platypus X chromosomes have substantial homology with the bird Z chromosome (including DMRT1), and to segments syntenic with this region in the human genome. {71:Veyrunes et al. (2008)} concluded that the therian X and Y chromosomes, including the SRY gene, evolved from an autosomal pair after the divergence of monotremes only 166 million years ago.
{36:Hughes et al. (2010)} finished sequencing the male-specific region of the Y chromosome (MSY) in chimpanzee, achieving levels of accuracy and completion previously reached for the human MSY. Comparison of the MSYs of the 2 species showed that they differ radically in sequence structure and gene content, indicating rapid evolution during the past 6 million years. The chimpanzee MSY contains twice as many massive palindromes as the human MSY, yet it has lost large fractions of the MSY protein-coding genes and gene families present in the last common ancestor. {36:Hughes et al. (2010)} suggested that the extraordinary divergence of the chimpanzee and human MSYs was driven by 4 synergistic factors: the prominent role of the MSY in sperm production, 'genetic hitchhiking' effects in the absence of meiotic crossingover, frequent ectopic recombination within the MSY, and species differences in mating behavior. | PMID:10431249,PMID:10459352,PMID:10602113,PMID:10843173,PMID:10852465,PMID:11278460,PMID:11641389,PMID:12107262,PMID:12111377,PMID:12764225,PMID:12793612,PMID:1339396,PMID:1406969,PMID:1415266,PMID:14628051,PMID:1483689,PMID:15687343,PMID:1570829,PMID:15863672,PMID:1619028,PMID:1634224,PMID:1639410,PMID:1695712,PMID:1734522,PMID:18454134,PMID:18463302,PMID:1956279,PMID:19737515,PMID:20072128,PMID:2028253,PMID:2030730,PMID:2247149,PMID:2247150,PMID:2247151,PMID:23446346,PMID:2374589,PMID:24009392,PMID:2401216,PMID:2594087,PMID:3464001,PMID:3545061,PMID:3690661,PMID:3738510,PMID:4161595,PMID:572812,PMID:5951402,PMID:7017147,PMID:7684656,PMID:7717397,PMID:7718558,PMID:7774012,PMID:7985018,PMID:7987333,PMID:8012385,PMID:8105086,PMID:8111368,PMID:8122913,PMID:8127908,PMID:8159753,PMID:8244390,PMID:8257986,PMID:8353496,PMID:8355783,PMID:8355784,PMID:8434602,PMID:8447323,PMID:8774960,PMID:8978769,PMID:9024280,PMID:9143916,PMID:9150734,PMID:9215677,PMID:9341880,PMID:9443877,PMID:9450909,PMID:9521592 |
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OMIM | UBIQUITIN-SPECIFIC PROTEASE 9, Y CHROMOSOME; USP9Y | DROSOPHILA FAT FACETS-RELATED, Y-LINKED; DFFRY, USP9Y, DFFRY, SPGFY2 | Spermatogenic failure, Y-linked, 2 | Y-linked | Y | {4:Jones et al. (1996)} reported that an expressed sequence tag (EST 221) derived from human adult testis shares homology with the Drosophila fat facets (faf) gene. They detected related sequences on both the human X and Y chromosomes. They used EST 221 to derive clones covering the complete open reading frame of the X-specific locus they termed DFFRX ({300072}). Y-specific cDNA clones were derived and the corresponding Y-specific locus designated DFFRY. Over the 2 regions corresponding to nucleotides 6 to 1901 and nucleotides 5815 to 7907 of the DFFRX sequence, the X- and Y-specific sequences share 91% and 88% identity, respectively. Both putative gene products contain conserved cysteine and histidine domains that have been described in ubiquitin C-terminal hydrolases (e.g., {191342}). {4:Jones et al. (1996)} mapped DFFRY to Yq11.2 by Southern analysis. They noted that in DFFRY there were multiple stop codons in the 3-prime region, suggesting that the Y locus may encode a truncated product or may represent a nonfunctional pseudogene. They detected expression of both DFFRX and DFFRY in developing human tissues. They found also that sequences detected by the EST 221 are widely expressed in adult human tissues.
The coding regions of the DFFRY and DFFRX genes show 89% identity at the nucleotide level. In common with DFFRX, the potential amino acid sequence of DFFRY contains the conserved cys and his domains characteristic of ubiquitin C-terminal hydrolases. The human DFFRY mRNA is expressed in a wide range of adult and embryonic tissues, including testis, whereas the homologous mouse Dffry gene is expressed specifically in the testis. {1:Brown et al. (1998)} found that 3 azoospermic male patients had deletion of DFFRY from the Y chromosome. Two patients had a testicular phenotype that resembled Sertoli cell-only type I (see {400042}), and the third (patient 'Sayer') had diminished spermatogenesis (see {400005.0002}). In all 3 patients, the deletions extended from close to the 3-prime end into the gene, removing the entire coding sequence of DFFRY. {1:Brown et al. (1998)} showed that the mouse Dffry gene maps to the Sxr-b deletion interval on the shorter arm of the mouse Y chromosome and that its expression in mouse testis can first be detected between 7.5 and 10.5 days after birth when type A and B spermatogonia and preleptotene and leptotene spermatocytes are present.
{6:Sargent et al. (1999)} refined the deletion breakpoints in 4 patients with AZFa male infertility. All patients had USP9Y and an anonymous EST, AZFaT1, deleted in their entirety, and 3 patients also had DBY ({400010}) deleted. The 3 patients with AZFaT1, USP9Y, and DBY deleted showed a severe Sertoli cell-only type I phenotype, whereas the patient who had retained DBY (SAYER, originally reported by {1:Brown et al., 1998}) showed a milder oligozoospermic phenotype (see {400005.0002}). RT-PCR analysis of mouse testis RNA showed that Dby is expressed primarily in somatic cells, while Usp9y is expressed specifically in testis in a germ cell-dependent fashion.
{8:Sun et al. (1999)} were the first to trace spermatogenic failure to a point mutation in a Y-linked gene or to a deletion of a single Y-linked gene. They sequenced the AZFa (see {415000}) region of the Y chromosome and identified 2 previously described functional genes: USP9Y and DBY ({400010}). Screening of the 2 genes in 576 infertile and 96 fertile men revealed several sequence variants, most of which appeared to be heritable and of little functional consequence. They found 1 de novo mutation in USP9Y ({400005.0001}): a 4-bp deletion in the splice donor site, causing an exon to be skipped and protein truncation. This mutation was present in a man with nonobstructive azoospermia, but was absent in his fertile brother, suggesting that the USP9Y mutation caused spermatogenic failure. {8:Sun et al. (1999)} also identified a single gene deletion associated with spermatogenic failure, again involving USP9Y, by reanalyzing the third patient (SAYER) from {1:Brown et al. (1998)}; see {400005.0002}.
{3:Foresta et al. (2000)} described a complete sequence map of the AZFa region, the genomic structure of AZFa genes, and their deletion analysis in 173 infertile men with well-defined spermatogenic alterations. Deletions were found in 9 patients: DBY alone was deleted in 6, USP9Y alone in one ({400005.0002}), and there was one each with USP9Y-DBY or DBY-UTY ({400009}) missing. No patients solely lacked UTY. Patients lacking DBY exhibited either Sertoli cell-only syndrome or severe hypospermatogenesis. Expression analysis of AZFa genes and their X homologs revealed ubiquitous expression for all of them except DBY; a shorter DBY transcript was expressed only in testis. The authors suggested that DBY plays a key role in the spermatogenic process.
In a worldwide sample of human Y chromosomes, {9:Thomson et al. (2000)} analyzed DNA sequence variation at 3 Y chromosome genes: SMCY ({426000}), DBY, and DFFRY. They used denaturing high-performance liquid chromatography to determine sequence variation at each locus. They focused on estimating the expected time to the most recent common ancestor, and the expected ages of certain mutations with interesting geographic distributions. Although the geographic structure of the inferred haplotype tree was reminiscent of that obtained for other loci (the root is in Africa, and most of the oldest non-African lineages are Asian), the expected time to the most recent common ancestor was found to be remarkably short, on the order of 50,000 years. They estimated that the spread of Y chromosomes out of Africa was much more recent than previously thought. Their data also indicated substantial population growth in the effective number of different human Y chromosomes.
By use of denaturing HPLC, {7:Shen et al. (2000)} screened the DFFRY, SMCY, DBY, and UTY1 genes for polymorphic markers in males representative of the 5 continents. Nucleotide diversity was found in the coding regions of 3 of the genes but was not observed in DBY. In agreement with most autosomal genes, diversity estimates for the noncoding regions were about 2- to 3-fold higher than those for coding regions. Pairwise nucleotide mismatch distributions dated the occurrence of population expansion to approximately 28,000 years ago.
In a normospermic man and his brother and father, {5:Luddi et al. (2009)} identified a deletion in the AZFa region that encompassed the USP9Y gene ({400005.0002}). The authors concluded that USP9Y is not essential for normal sperm production and fertility in humans. | PMID:10402373,PMID:10507722,PMID:10581029,PMID:10767340,PMID:10861003,PMID:10861004,PMID:19246359,PMID:8922996,PMID:9384609 |
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OMIM | RIBOSOMAL PROTEIN S6 KINASE, 90-KD, 3; RPS6KA3 | RIBOSOMAL S6 KINASE 2; RSK2;;
MITOGEN-ACTIVATED PROTEIN KINASE-ACTIVATED PROTEIN KINASE 1B; MAPKAPK1B;;
MAPKAP KINASE 1B;;
ISPK1, RPS6KA3, RSK2, MRX19 | Mental retardation, X-linked 19 | | X | {11:Jacquot et al. (1998)} found that the open reading frame of the RPS6KA3 coding region contains 22 exons.|* {2:Bjorbaek et al. (1995)} showed that the cDNA encoding RPS6KA3, which they called ISPK1, encodes a predicted protein of 740 amino acids.
{28:Zeniou et al. (2002)} determined the expression of the RSK1 (RPS6KA1; {601684}), RSK2, and RSK3 (RPS6KA2; {601685}) genes in various human tissues, during mouse embryogenesis, and in mouse brain. The 3 RSK mRNAs were expressed in all human tissues and brain regions tested, supporting functional redundancy. However, tissue-specific variations in levels suggested that the proteins may also serve specific roles. The mouse Rsk3 gene was prominently expressed in the developing neural and sensory tissues, whereas Rsk1 gene expression was the strongest in various other tissues with high proliferative activity, suggesting distinct roles during development. In adult mouse brain, the highest levels of Rsk2 expression were observed in regions with high synaptic activity, including the neocortex, the hippocampus, and Purkinje cells. The authors suggested that in these areas, which are essential to cognitive function and learning, the RSK1 and RSK3 genes may not be able to fully compensate for a lack of RSK2 function.|* During the immediate-early response of mammalian cells to mitogens, histone H3 (see {602810}) is rapidly and transiently phosphorylated by one or more kinases. {23:Sassone-Corsi et al. (1999)} demonstrated that RSK2 was required for epidermal growth factor (EGF; {131530})-stimulated phosphorylation of H3. Fibroblasts derived from a CLS patient failed to exhibit EGF-stimulated phosphorylation of H3, although H3 was phosphorylated during mitosis. Introduction of the wildtype RSK2 gene restored EGF-stimulated phosphorylation of H3 in the CLS cells. In addition, disruption of the RSK2 gene by homologous recombination in murine embryonic stem cells abolished EGF-stimulated phosphorylation of H3. H3 appears to be a direct or indirect target of RSK2, suggesting to {23:Sassone-Corsi et al. (1999)} that chromatin remodeling might contribute to mitogen-activated protein kinase-regulated gene expression.
{24:Thomas et al. (2005)} presented evidence suggesting that RSK2 is involved in regulation of excitatory AMPA receptor synaptic transmission by interacting with and phosphorylating PDZ domain-containing proteins.
Spindle assembly checkpoint (SAC) prevents anaphase onset until all chromosomes have successfully attached to spindle microtubules. Using Xenopus egg extracts and HeLa cells, {26:Vigneron et al. (2010)} found that RSK2 had a role in spindle assembly checkpoint. RSK2 localized to kinetochores during SAC. Immunofluorescence analysis and knockdown studies revealed that RSK2 and Aurora B (AURKB; {604970}) depended upon each other for kinetochore localization. Association of RSK2 at kinetochores was required to maintain SAC activation and localization of MAD1 (MXD1; {600021}), MAD2 (MAD2L1; {601467}), and CENPE ({117143}) at kinetochores. Expression of Xenopus Rsk2 rescued the effects of RSK2 knockdown in HeLa cells.|* In a study of the region of the X chromosome (Xp22.2) within which the Coffin-Lowry syndrome (CLS; {303600}) maps, {25:Trivier et al. (1996)} identified an expressed sequence tag (EST) that showed 100% homology with a cDNA coding for RPS6KA3. Its localization was independently confirmed by {2:Bjorbaek et al. (1995)}.|* Coffin-Lowry Syndrome
The localization of the RSK2 gene within the Coffin-Lowry syndrome (CLS; {303600}) interval, together with its role in signaling pathways, prompted {25:Trivier et al. (1996)} to investigate its possible implication in CLS. Patient samples from 76 families were screened, and 1 patient was found to have a genomic deletion of approximately 2 kb. Amplification by RT-PCR of cDNA from the patient and direct sequencing showed a deletion of 187 bp between nucleotide positions 406 and 593 ({300075.0001}). The deletion produced a frameshift, generating a TAA termination codon 33 bp downstream of the deletion junction. The mutation cosegregated with CLS in 2 affected males and 1 female with discrete manifestations in this family. {25:Trivier et al. (1996)} then searched for point mutations and found both nonsense and missense mutations. Tissue-specific differences in gene expression suggested distinct physiologic roles for the various members of the RSK family ({21:Moller et al., 1994}; {30:Zhao et al., 1995}). RSK3 differs with respect to substrate specificity from other RSKs and may also have distinct upstream activators. {25:Trivier et al. (1996)} noted that in CLS, RSK1 and RSK3 are expressed at levels equivalent to those in normal individuals, indicating that they are not capable of overcoming the RSK2 deficiency. However, no abnormality of glycogen metabolism was found in CLS patients, although RSK2 was shown to be responsible for the activation of glycogen synthesis ({6:Dent et al., 1990}).
{11:Jacquot et al. (1998)} designed primers for PCR amplification of single exons from genomic DNA and subsequent SSCP analysis. They screened 37 patients with clinical features suggestive of CLS; 25 nucleotide changes predicted to be disease-causing mutations were identified, including 8 splice site alterations, 7 nonsense mutations, 5 frameshift mutations, and 5 missense mutations. Of the 25 mutations, 23 were novel. Coupled with previously reported mutations, these findings brought the total of different RSK2 mutations to 34. These were distributed throughout the RSK2 gene, with no clustering, and all but 2, which were found in 2 independent patients, were unique. A very high (68%) rate of de novo mutations was observed. Three mutations were found in female probands with no affected male relatives; these patients were ascertained through learning disability and mild but suggestive facial and digital dysmorphisms. No obvious correlation was observed between the position or type of the RSK2 mutations and the severity or particular clinical features of CLS.
{1:Abidi et al. (1999)} tested 5 unrelated individuals with CLS for mutations in 9 exons of the RSK2 gene using SSCP analysis. Two patients had the same missense mutation, 340C-T, predicted to cause an arg114-to-trp amino acid change ({300075.0006}). This mutation falls just outside the N-terminal ATP-binding site in a highly conserved region of the protein and may lead to structural changes since tryptophan has an aromatic side chain whereas arginine is a 5-carbon basic amino acid. The third patient had a 2186G-A nucleotide change, resulting in an arg729-to-gln missense mutation ({300075.0009}). The fourth patient had a 2-bp deletion (AG) of bases 451 and 452 ({300075.0007}). This created a frameshift that resulted in a stop codon 25 amino acids downstream, thereby producing a truncated protein. This deletion also falls within the highly conserved amino-catalytic domain of the protein. The fifth patient had a 2065C-T nucleotide change that resulted in a premature stop codon, thereby producing a truncated protein ({300075.0008}). Three of the patients in whom RSK2 mutations were identified by {1:Abidi et al. (1999)} had at least 1 brother who also carried the diagnosis of CLS. One of the 5 patients had a family history of mental retardation in male relatives, and his mother and aunt had been assessed as having intellectual impairment. All of the probands had large, soft hands with tapering fingers, severe to moderate mental retardation, short stature below the 5th centile, weight below the 5th centile, microcephaly, telecanthus or hypertelorism, and prominent eyes. Two were Caucasian; in these probands large mouth and prominent lower lips were observed. For the 3 African American probands this was difficult to evaluate because of the ethnic background.
{10:Harum et al. (2001)} noted that, based on evidence from experimental models, the transcription factor cAMP response element-binding protein (CREB; {123810}) is thought to be involved in memory formation. RSK2 activates CREB through phosphorylation at serine-133. In 7 patients with CLS (5 boys and 2 girls), {10:Harum et al. (2001)} found a diminished activity of RSK2 to phosphorylate a CREB-like peptide in vitro in all cells lines. The authors noted a linear correlation between RSK2 activation of CREB and cognitive levels of the patients, consistent with the hypothesis that CREB is involved in human learning and memory. Other characteristics of the syndrome, including facial and bony abnormalities, may be due to impaired expression of various CREB-responsive genes.
By screening 250 patients with clinical features suggestive of Coffin-Lowry syndrome, {4:Delaunoy et al. (2001)} identified 71 distinct disease-associated RSK2 mutations in 86 unrelated families; 38% of the mutations were missense mutations, 20% were nonsense mutations, 18% were splicing errors, and 21% were short deletions or insertions. About 57% of the mutations resulted in premature translation termination, and most predicted loss of function of the mutant allele. The changes were distributed throughout the RSK2 gene and showed no obvious clustering or phenotypic association. However, some missense mutations were associated with milder phenotypes; in 1 family, 1 such mutation was associated solely with mild mental retardation. Nine mutations were found in female probands, with no affected male relatives, who had learning disability and mild facial and digital dysmorphism.
{29:Zeniou et al. (2002)} pointed out that in a series of 250 patients screened by SSCP analysis in whom the clinical diagnosis of CLS was made ({4:Delaunoy et al., 2001}), no mutations were detected in 165 (66%). To determine what proportion of these latter patients had an RSK2 mutation that had not been detected and what proportion have different disorders that are phenotypically similar to CLS, {29:Zeniou et al. (2002)} investigated, by Western blot analysis and in vitro kinase assay, cell lines from 26 patients in whom no mutation was previously identified by SSCP analysis. This approach allowed them to identify 7 novel RSK2 mutations: 2 changes in the coding sequence of RSK2, 1 intragenic deletion, and 4 unusual intronic nucleotide substitutions that did not affect the consensus GT or AG splice sites. No disease-causing nucleotide change was identified in the promoter region of the RSK2 gene. The results suggested that some patients have a disorder that is phenotypically very similar to CLS but is not caused by RSK2 defects.
{5:Delaunoy et al. (2006)} analyzed the RPS6KA3 gene in 120 patients with CLS and identified 45 mutations, of which 44 were novel, confirming the high rate of new mutations at the RSK2 locus. The authors noted that no mutation was found in over 60% of the patients referred to them for screening. {5:Delaunoy et al. (2006)} stated that of the 128 CLS mutations reported to date, 33% are missense mutations, 15% nonsense mutations, 20% splicing errors, and 29% short deletion or insertion events; and 4 large deletions have been reported. The mutations are distributed throughout the RPS6KA3 gene, and most mutations are private.
In a patient with a clinical phenotype highly suggestive of CLS in whom no mutation had been identified by sequencing PCR-amplified exons of RPS6KA3 from genomic DNA, {15:Marques Pereira et al. (2007)} analyzed the gene by direct sequencing of overlapping RT-PCR products and identified a direct tandem duplication spanning exactly exons 17 to 20 ({300075.0019}). The authors stated that this was the first reported large duplication in the RPS6KA3 gene.
X-Linked Mental Retardation 19
In affected members of a family with nonsyndromic X-linked mental retardation-19 (MRX19; {300844}), {20:Merienne et al. (1999)} identified a missense mutation ({300075.0010}) in the RPS6KA3 gene. Patients exhibited none of the facial, digital, or skeletal features or the abnormal posture or gait typical of Coffin-Lowry syndrome.
{8:Field et al. (2006)} identified 3 different mutations in the RPS6KA3 gene (see, e.g., {300075.0020}-{300075.0021}) in affected members of 3 unrelated families with nonsyndromic X-linked mental retardation. The patients had some variable features reminiscent of Coffin-Lowry syndrome, such as coarse facial features, kyphoscoliosis, short stature, and some redundancy of palmar skin with horizontal creases, but these additional features were considered to be too mild or atypical for a diagnosis of CLS.|* The level of residual RPS6KA3 activity seems to be related to the severity of the phenotype. {20:Merienne et al. (1999)} demonstrated 10 to 20% residual enzymatic activity in patients with nonsyndromic MRX19, which was postulated to result in the relatively mild phenotype without skeletal anomalies ({300075.0010}). The patients reported by {8:Field et al. (2006)} with nonsyndromic X-linked mental retardation also had a milder phenotype, which the authors thought likely resulted from residual protein activity. {8:Field et al. (2006)} noted that the mutations in their report and the mutation ({300075.0011}) reported by {13:Manouvrier-Hanu et al. (1999)} in a family with mild Coffin-Lowry syndrome were small in-frame deletions or missense mutations affecting the serine/threonine kinase domain. {8:Field et al. (2006)} hypothesized that the presence of a small amount of residual enzymatic activity may be sufficient to maintain normal osteoblast differentiation and ameliorate the skeletal phenotype associated with CLS. The level of residual enzymatic activity has also been linked to cognitive performance, with higher levels being associated with a higher level of intellectual function ({10:Harum et al., 2001}).|* The RPS6KA3 gene encodes a member of the RSK (ribosomal S6 kinase) family of growth factor-regulated serine/threonine kinases, known also as p90(rsk). RSK proteins contain 2 functional kinase catalytic domains: the N-terminal kinase domain belongs to the AGC kinase family (see {188830}), and the C-terminal kinase domain belongs to the CamK family (see {604998}). The kinase domains are connected by a 100-amino acid linker region containing a PDK (PDPK1; {605213}) docking site. RSK proteins are directly phosphorylated and activated by MAPK proteins (e.g., ERK1; {601795}) in response to growth factors, polypeptide hormones, and neurotransmitters, and then subsequently phosphorylate many substrates. RSKs appear to have important roles in cell cycle progression, differentiation, and cell survival (review by {16:Marques Pereira et al., 2010}).|* Using Rsk2 -/- mice, {27:Yang et al. (2004)} showed that RSK2 is required for osteoblast differentiation and function. They identified the transcription factor ATF4 ({604064}) as a critical substrate of RSK2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression. Additionally, RSK2 and ATF4 were found to posttranscriptionally regulate the synthesis of type I collagen (see {120150}), the main constituent of the bone matrix. Accordingly, Atf4 deficiency in mice resulted in delayed bone formation during embryonic development and low bone mass throughout postnatal life. {27:Yang et al. (2004)} concluded that ATF4 is a critical regulator of osteoblast differentiation and function and that lack of ATF4 phosphorylation by RSK2 may contribute to the skeletal phenotype of Coffin-Lowry syndrome.
{3:David et al. (2005)} demonstrated that Rsk2-null mice develop progressive osteopenia due to impaired osteoblast function and normal osteoclast differentiation. They also observed that c-fos ({164810})-dependent osteosarcoma formation was impaired in the absence of Rsk2; the lack of c-fos phosphorylation led to reduced c-fos protein levels, which were thought to be responsible for the observed decreased proliferation and increased apoptosis of transformed osteoblasts. {3:David et al. (2005)} concluded that Rsk2-dependent stabilization of c-fos is essential for osteosarcoma formation in mice.
{22:Poirier et al. (2007)} found that Rsk2-null mice showed a mild impairment in spatial working memory, delayed acquisition of a spatial reference memory task, and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. The studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-null mice. There were no obvious brain abnormalities at the anatomic and histologic level. The behavioral changes observed supported a role for Rsk2 in cognitive functions.
{14:Marques Pereira et al. (2008)} found that Rsk2-null mice had increased cortical dopamine levels and overexpression of the DRD2 receptor ({126450}) and dopamine transporter (SLC6A3; {126455}). Evidence also suggested that the dopaminergic dysregulation may have been caused, at least in part, by increased tyrosine hydroxylase (TH; {191290}) hyperactivity. The authors suggested that these neurotransmitters changes may explain some of the cognitive alterations in Rsk2-null mice.
Using microarray analysis, {19:Mehmood et al. (2011)} identified 100 genes that were differentially expressed in Rsk2 -/- mice compared with wildtype, and they confirmed differential expression of 24 of these genes using quantitative RT-PCR. Genes that were affected by Rsk2 deletion had roles in cell differentiation, proliferation, apoptosis, cell cycle, free radical scavenging, and nervous system development and function. {19:Mehmood et al. (2011)} characterized the consequences of 2-fold upregulation of the Gria2 gene ({138247}), which encodes a subunit of the AMPA glutamate receptor. Immunohistochemical analysis revealed significantly increased surface expression of Gria2 protein in Rsk2 -/- neurons. However, patch-clamp analysis showed significantly decreased basal AMPA receptor-mediated transmission in Rsk2 -/- hippocampal neurons. These changes in Gria2 protein expression and function appeared to be due to altered Gria2 mRNA editing and splicing in Rsk2 -/- mice. | PMID:10094187,PMID:10319851,PMID:10436156,PMID:10528858,PMID:11160957,PMID:11180593,PMID:11992250,PMID:12393804,PMID:12439904,PMID:12558110,PMID:14986828,PMID:15109498,PMID:15214012,PMID:15719069,PMID:16217014,PMID:16879200,PMID:17033934,PMID:17100996,PMID:17717706,PMID:18823370,PMID:19888300,PMID:20383198,PMID:21116650,PMID:2123524,PMID:7623830,PMID:7813820,PMID:8141249,PMID:8955270,PMID:9837815,PMID:9887375 |
|
OMIM | RIBOSOMAL PROTEIN S6 KINASE, 90-KD, 3; RPS6KA3 | RIBOSOMAL S6 KINASE 2; RSK2;;
MITOGEN-ACTIVATED PROTEIN KINASE-ACTIVATED PROTEIN KINASE 1B; MAPKAPK1B;;
MAPKAP KINASE 1B;;
ISPK1, RPS6KA3, RSK2, MRX19 | Coffin-Lowry syndrome | Isolated cases; X-linked dominant | X | {11:Jacquot et al. (1998)} found that the open reading frame of the RPS6KA3 coding region contains 22 exons.|* {2:Bjorbaek et al. (1995)} showed that the cDNA encoding RPS6KA3, which they called ISPK1, encodes a predicted protein of 740 amino acids.
{28:Zeniou et al. (2002)} determined the expression of the RSK1 (RPS6KA1; {601684}), RSK2, and RSK3 (RPS6KA2; {601685}) genes in various human tissues, during mouse embryogenesis, and in mouse brain. The 3 RSK mRNAs were expressed in all human tissues and brain regions tested, supporting functional redundancy. However, tissue-specific variations in levels suggested that the proteins may also serve specific roles. The mouse Rsk3 gene was prominently expressed in the developing neural and sensory tissues, whereas Rsk1 gene expression was the strongest in various other tissues with high proliferative activity, suggesting distinct roles during development. In adult mouse brain, the highest levels of Rsk2 expression were observed in regions with high synaptic activity, including the neocortex, the hippocampus, and Purkinje cells. The authors suggested that in these areas, which are essential to cognitive function and learning, the RSK1 and RSK3 genes may not be able to fully compensate for a lack of RSK2 function.|* During the immediate-early response of mammalian cells to mitogens, histone H3 (see {602810}) is rapidly and transiently phosphorylated by one or more kinases. {23:Sassone-Corsi et al. (1999)} demonstrated that RSK2 was required for epidermal growth factor (EGF; {131530})-stimulated phosphorylation of H3. Fibroblasts derived from a CLS patient failed to exhibit EGF-stimulated phosphorylation of H3, although H3 was phosphorylated during mitosis. Introduction of the wildtype RSK2 gene restored EGF-stimulated phosphorylation of H3 in the CLS cells. In addition, disruption of the RSK2 gene by homologous recombination in murine embryonic stem cells abolished EGF-stimulated phosphorylation of H3. H3 appears to be a direct or indirect target of RSK2, suggesting to {23:Sassone-Corsi et al. (1999)} that chromatin remodeling might contribute to mitogen-activated protein kinase-regulated gene expression.
{24:Thomas et al. (2005)} presented evidence suggesting that RSK2 is involved in regulation of excitatory AMPA receptor synaptic transmission by interacting with and phosphorylating PDZ domain-containing proteins.
Spindle assembly checkpoint (SAC) prevents anaphase onset until all chromosomes have successfully attached to spindle microtubules. Using Xenopus egg extracts and HeLa cells, {26:Vigneron et al. (2010)} found that RSK2 had a role in spindle assembly checkpoint. RSK2 localized to kinetochores during SAC. Immunofluorescence analysis and knockdown studies revealed that RSK2 and Aurora B (AURKB; {604970}) depended upon each other for kinetochore localization. Association of RSK2 at kinetochores was required to maintain SAC activation and localization of MAD1 (MXD1; {600021}), MAD2 (MAD2L1; {601467}), and CENPE ({117143}) at kinetochores. Expression of Xenopus Rsk2 rescued the effects of RSK2 knockdown in HeLa cells.|* In a study of the region of the X chromosome (Xp22.2) within which the Coffin-Lowry syndrome (CLS; {303600}) maps, {25:Trivier et al. (1996)} identified an expressed sequence tag (EST) that showed 100% homology with a cDNA coding for RPS6KA3. Its localization was independently confirmed by {2:Bjorbaek et al. (1995)}.|* Coffin-Lowry Syndrome
The localization of the RSK2 gene within the Coffin-Lowry syndrome (CLS; {303600}) interval, together with its role in signaling pathways, prompted {25:Trivier et al. (1996)} to investigate its possible implication in CLS. Patient samples from 76 families were screened, and 1 patient was found to have a genomic deletion of approximately 2 kb. Amplification by RT-PCR of cDNA from the patient and direct sequencing showed a deletion of 187 bp between nucleotide positions 406 and 593 ({300075.0001}). The deletion produced a frameshift, generating a TAA termination codon 33 bp downstream of the deletion junction. The mutation cosegregated with CLS in 2 affected males and 1 female with discrete manifestations in this family. {25:Trivier et al. (1996)} then searched for point mutations and found both nonsense and missense mutations. Tissue-specific differences in gene expression suggested distinct physiologic roles for the various members of the RSK family ({21:Moller et al., 1994}; {30:Zhao et al., 1995}). RSK3 differs with respect to substrate specificity from other RSKs and may also have distinct upstream activators. {25:Trivier et al. (1996)} noted that in CLS, RSK1 and RSK3 are expressed at levels equivalent to those in normal individuals, indicating that they are not capable of overcoming the RSK2 deficiency. However, no abnormality of glycogen metabolism was found in CLS patients, although RSK2 was shown to be responsible for the activation of glycogen synthesis ({6:Dent et al., 1990}).
{11:Jacquot et al. (1998)} designed primers for PCR amplification of single exons from genomic DNA and subsequent SSCP analysis. They screened 37 patients with clinical features suggestive of CLS; 25 nucleotide changes predicted to be disease-causing mutations were identified, including 8 splice site alterations, 7 nonsense mutations, 5 frameshift mutations, and 5 missense mutations. Of the 25 mutations, 23 were novel. Coupled with previously reported mutations, these findings brought the total of different RSK2 mutations to 34. These were distributed throughout the RSK2 gene, with no clustering, and all but 2, which were found in 2 independent patients, were unique. A very high (68%) rate of de novo mutations was observed. Three mutations were found in female probands with no affected male relatives; these patients were ascertained through learning disability and mild but suggestive facial and digital dysmorphisms. No obvious correlation was observed between the position or type of the RSK2 mutations and the severity or particular clinical features of CLS.
{1:Abidi et al. (1999)} tested 5 unrelated individuals with CLS for mutations in 9 exons of the RSK2 gene using SSCP analysis. Two patients had the same missense mutation, 340C-T, predicted to cause an arg114-to-trp amino acid change ({300075.0006}). This mutation falls just outside the N-terminal ATP-binding site in a highly conserved region of the protein and may lead to structural changes since tryptophan has an aromatic side chain whereas arginine is a 5-carbon basic amino acid. The third patient had a 2186G-A nucleotide change, resulting in an arg729-to-gln missense mutation ({300075.0009}). The fourth patient had a 2-bp deletion (AG) of bases 451 and 452 ({300075.0007}). This created a frameshift that resulted in a stop codon 25 amino acids downstream, thereby producing a truncated protein. This deletion also falls within the highly conserved amino-catalytic domain of the protein. The fifth patient had a 2065C-T nucleotide change that resulted in a premature stop codon, thereby producing a truncated protein ({300075.0008}). Three of the patients in whom RSK2 mutations were identified by {1:Abidi et al. (1999)} had at least 1 brother who also carried the diagnosis of CLS. One of the 5 patients had a family history of mental retardation in male relatives, and his mother and aunt had been assessed as having intellectual impairment. All of the probands had large, soft hands with tapering fingers, severe to moderate mental retardation, short stature below the 5th centile, weight below the 5th centile, microcephaly, telecanthus or hypertelorism, and prominent eyes. Two were Caucasian; in these probands large mouth and prominent lower lips were observed. For the 3 African American probands this was difficult to evaluate because of the ethnic background.
{10:Harum et al. (2001)} noted that, based on evidence from experimental models, the transcription factor cAMP response element-binding protein (CREB; {123810}) is thought to be involved in memory formation. RSK2 activates CREB through phosphorylation at serine-133. In 7 patients with CLS (5 boys and 2 girls), {10:Harum et al. (2001)} found a diminished activity of RSK2 to phosphorylate a CREB-like peptide in vitro in all cells lines. The authors noted a linear correlation between RSK2 activation of CREB and cognitive levels of the patients, consistent with the hypothesis that CREB is involved in human learning and memory. Other characteristics of the syndrome, including facial and bony abnormalities, may be due to impaired expression of various CREB-responsive genes.
By screening 250 patients with clinical features suggestive of Coffin-Lowry syndrome, {4:Delaunoy et al. (2001)} identified 71 distinct disease-associated RSK2 mutations in 86 unrelated families; 38% of the mutations were missense mutations, 20% were nonsense mutations, 18% were splicing errors, and 21% were short deletions or insertions. About 57% of the mutations resulted in premature translation termination, and most predicted loss of function of the mutant allele. The changes were distributed throughout the RSK2 gene and showed no obvious clustering or phenotypic association. However, some missense mutations were associated with milder phenotypes; in 1 family, 1 such mutation was associated solely with mild mental retardation. Nine mutations were found in female probands, with no affected male relatives, who had learning disability and mild facial and digital dysmorphism.
{29:Zeniou et al. (2002)} pointed out that in a series of 250 patients screened by SSCP analysis in whom the clinical diagnosis of CLS was made ({4:Delaunoy et al., 2001}), no mutations were detected in 165 (66%). To determine what proportion of these latter patients had an RSK2 mutation that had not been detected and what proportion have different disorders that are phenotypically similar to CLS, {29:Zeniou et al. (2002)} investigated, by Western blot analysis and in vitro kinase assay, cell lines from 26 patients in whom no mutation was previously identified by SSCP analysis. This approach allowed them to identify 7 novel RSK2 mutations: 2 changes in the coding sequence of RSK2, 1 intragenic deletion, and 4 unusual intronic nucleotide substitutions that did not affect the consensus GT or AG splice sites. No disease-causing nucleotide change was identified in the promoter region of the RSK2 gene. The results suggested that some patients have a disorder that is phenotypically very similar to CLS but is not caused by RSK2 defects.
{5:Delaunoy et al. (2006)} analyzed the RPS6KA3 gene in 120 patients with CLS and identified 45 mutations, of which 44 were novel, confirming the high rate of new mutations at the RSK2 locus. The authors noted that no mutation was found in over 60% of the patients referred to them for screening. {5:Delaunoy et al. (2006)} stated that of the 128 CLS mutations reported to date, 33% are missense mutations, 15% nonsense mutations, 20% splicing errors, and 29% short deletion or insertion events; and 4 large deletions have been reported. The mutations are distributed throughout the RPS6KA3 gene, and most mutations are private.
In a patient with a clinical phenotype highly suggestive of CLS in whom no mutation had been identified by sequencing PCR-amplified exons of RPS6KA3 from genomic DNA, {15:Marques Pereira et al. (2007)} analyzed the gene by direct sequencing of overlapping RT-PCR products and identified a direct tandem duplication spanning exactly exons 17 to 20 ({300075.0019}). The authors stated that this was the first reported large duplication in the RPS6KA3 gene.
X-Linked Mental Retardation 19
In affected members of a family with nonsyndromic X-linked mental retardation-19 (MRX19; {300844}), {20:Merienne et al. (1999)} identified a missense mutation ({300075.0010}) in the RPS6KA3 gene. Patients exhibited none of the facial, digital, or skeletal features or the abnormal posture or gait typical of Coffin-Lowry syndrome.
{8:Field et al. (2006)} identified 3 different mutations in the RPS6KA3 gene (see, e.g., {300075.0020}-{300075.0021}) in affected members of 3 unrelated families with nonsyndromic X-linked mental retardation. The patients had some variable features reminiscent of Coffin-Lowry syndrome, such as coarse facial features, kyphoscoliosis, short stature, and some redundancy of palmar skin with horizontal creases, but these additional features were considered to be too mild or atypical for a diagnosis of CLS.|* The level of residual RPS6KA3 activity seems to be related to the severity of the phenotype. {20:Merienne et al. (1999)} demonstrated 10 to 20% residual enzymatic activity in patients with nonsyndromic MRX19, which was postulated to result in the relatively mild phenotype without skeletal anomalies ({300075.0010}). The patients reported by {8:Field et al. (2006)} with nonsyndromic X-linked mental retardation also had a milder phenotype, which the authors thought likely resulted from residual protein activity. {8:Field et al. (2006)} noted that the mutations in their report and the mutation ({300075.0011}) reported by {13:Manouvrier-Hanu et al. (1999)} in a family with mild Coffin-Lowry syndrome were small in-frame deletions or missense mutations affecting the serine/threonine kinase domain. {8:Field et al. (2006)} hypothesized that the presence of a small amount of residual enzymatic activity may be sufficient to maintain normal osteoblast differentiation and ameliorate the skeletal phenotype associated with CLS. The level of residual enzymatic activity has also been linked to cognitive performance, with higher levels being associated with a higher level of intellectual function ({10:Harum et al., 2001}).|* The RPS6KA3 gene encodes a member of the RSK (ribosomal S6 kinase) family of growth factor-regulated serine/threonine kinases, known also as p90(rsk). RSK proteins contain 2 functional kinase catalytic domains: the N-terminal kinase domain belongs to the AGC kinase family (see {188830}), and the C-terminal kinase domain belongs to the CamK family (see {604998}). The kinase domains are connected by a 100-amino acid linker region containing a PDK (PDPK1; {605213}) docking site. RSK proteins are directly phosphorylated and activated by MAPK proteins (e.g., ERK1; {601795}) in response to growth factors, polypeptide hormones, and neurotransmitters, and then subsequently phosphorylate many substrates. RSKs appear to have important roles in cell cycle progression, differentiation, and cell survival (review by {16:Marques Pereira et al., 2010}).|* Using Rsk2 -/- mice, {27:Yang et al. (2004)} showed that RSK2 is required for osteoblast differentiation and function. They identified the transcription factor ATF4 ({604064}) as a critical substrate of RSK2 that is required for the timely onset of osteoblast differentiation, for terminal differentiation of osteoblasts, and for osteoblast-specific gene expression. Additionally, RSK2 and ATF4 were found to posttranscriptionally regulate the synthesis of type I collagen (see {120150}), the main constituent of the bone matrix. Accordingly, Atf4 deficiency in mice resulted in delayed bone formation during embryonic development and low bone mass throughout postnatal life. {27:Yang et al. (2004)} concluded that ATF4 is a critical regulator of osteoblast differentiation and function and that lack of ATF4 phosphorylation by RSK2 may contribute to the skeletal phenotype of Coffin-Lowry syndrome.
{3:David et al. (2005)} demonstrated that Rsk2-null mice develop progressive osteopenia due to impaired osteoblast function and normal osteoclast differentiation. They also observed that c-fos ({164810})-dependent osteosarcoma formation was impaired in the absence of Rsk2; the lack of c-fos phosphorylation led to reduced c-fos protein levels, which were thought to be responsible for the observed decreased proliferation and increased apoptosis of transformed osteoblasts. {3:David et al. (2005)} concluded that Rsk2-dependent stabilization of c-fos is essential for osteosarcoma formation in mice.
{22:Poirier et al. (2007)} found that Rsk2-null mice showed a mild impairment in spatial working memory, delayed acquisition of a spatial reference memory task, and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. The studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-null mice. There were no obvious brain abnormalities at the anatomic and histologic level. The behavioral changes observed supported a role for Rsk2 in cognitive functions.
{14:Marques Pereira et al. (2008)} found that Rsk2-null mice had increased cortical dopamine levels and overexpression of the DRD2 receptor ({126450}) and dopamine transporter (SLC6A3; {126455}). Evidence also suggested that the dopaminergic dysregulation may have been caused, at least in part, by increased tyrosine hydroxylase (TH; {191290}) hyperactivity. The authors suggested that these neurotransmitters changes may explain some of the cognitive alterations in Rsk2-null mice.
Using microarray analysis, {19:Mehmood et al. (2011)} identified 100 genes that were differentially expressed in Rsk2 -/- mice compared with wildtype, and they confirmed differential expression of 24 of these genes using quantitative RT-PCR. Genes that were affected by Rsk2 deletion had roles in cell differentiation, proliferation, apoptosis, cell cycle, free radical scavenging, and nervous system development and function. {19:Mehmood et al. (2011)} characterized the consequences of 2-fold upregulation of the Gria2 gene ({138247}), which encodes a subunit of the AMPA glutamate receptor. Immunohistochemical analysis revealed significantly increased surface expression of Gria2 protein in Rsk2 -/- neurons. However, patch-clamp analysis showed significantly decreased basal AMPA receptor-mediated transmission in Rsk2 -/- hippocampal neurons. These changes in Gria2 protein expression and function appeared to be due to altered Gria2 mRNA editing and splicing in Rsk2 -/- mice. | PMID:10094187,PMID:10319851,PMID:10436156,PMID:10528858,PMID:11160957,PMID:11180593,PMID:11992250,PMID:12393804,PMID:12439904,PMID:12558110,PMID:14986828,PMID:15109498,PMID:15214012,PMID:15719069,PMID:16217014,PMID:16879200,PMID:17033934,PMID:17100996,PMID:17717706,PMID:18823370,PMID:19888300,PMID:20383198,PMID:21116650,PMID:2123524,PMID:7623830,PMID:7813820,PMID:8141249,PMID:8955270,PMID:9837815,PMID:9887375 |
|
OMIM | PHOSPHATE-REGULATING ENDOPEPTIDASE HOMOLOG, X-LINKED; PHEX | PEX, PHEX, HYP, HPDR1, LXHR | Hypophosphatemic rickets, X-linked dominant | X-linked dominant | X | {24:Holm et al. (1997)} determined that the PHEX gene contains 18 exons. Its genomic organization shares similarity with members of the family of neutral endopeptidases.|* In 3 unrelated patients with X-linked hypophosphatemic rickets ({307800}), the {25:HYP Consortium (1995)} identified 3 different mutations in the PHEX gene ({300550.0001}-{300550.0003}).
{24:Holm et al. (1997)} identified mutations in the PHEX gene in 9 of 22 unrelated patients with X-linked hypophosphatemic rickets: 3 nonsense mutations, a 1-bp deletion leading to a frameshift, a donor-splice site mutation, and missense mutations in 4 patients (see, e.g., {300550.0004}-{300550.0006}).
{12:Dixon et al. (1998)} identified a total of 31 mutations in the PHEX gene in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH. Thirty of the mutations were scattered throughout the putative extracellular domain. {12:Dixon et al. (1998)} also identified 6 PHEX polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The majority (over 70%) of the mutations were predicted to result in a functional loss of the PHEX protein, rather than haploinsufficiency or a dominant-negative effect.
{18:Filisetti et al. (1999)} reported 30 newly detected mutations in the PHEX gene, and pooled findings with all previously published mutations. The spectrum of the mutations displayed 16% deletions, 8% insertions, 34% missense, 27% nonsense, and 15% splice site mutations, with peaks in exons 15 and 17. Since 32.8% of PHEX amino acids are conserved in the family of the endopeptidases, the number of missense mutations detected at nonconserved residues was smaller than expected, whereas the number of nonsense mutations observed at nonconserved residues was very close to the expected number. Compared with conserved amino acids, the changes in nonconserved amino acids may result in benign polymorphisms or possibly mild disease that may go undiagnosed.
{39:Sabbagh et al. (2000)} stated that 131 HYP-causing mutations in the PHEX gene had been reported. They announced the creation of an online PHEX mutation database for the collection and distribution of information on PHEX mutations.
{37:Sabbagh et al. (2001)} examined the effect of PHEX missense mutations on cellular trafficking of the recombinant protein. Four mutant PHEX cDNAs were generated by PCR mutagenesis (e.g., E581V). Three of the mutants were completely sensitive to endoglycosidase H digestion, indicating that they were not fully glycosylated. Sequestration of the disease-causing mutant proteins in the endoplasmic reticulum and plasma membrane localization of wildtype PHEX proteins was demonstrated by immunofluorescence and cell surface biotinylation. {36:Sabbagh et al. (2003)} assessed the impact of 9 PHEX missense mutations on cellular trafficking, endopeptidase activity, and protein conformation. Eight mutations had been identified in XLH patients; the remaining mutation, E581V, had been engineered in NEP ({120520}), to which PHEX shows significant homology, where it was shown to abolish catalytic activity but not interfere with cell surface localization of the recombinant protein ({11:Devault et al., 1988}). The authors demonstrated that some mutations in secreted PHEX abrogate catalytic activity, whereas others alter the trafficking and conformation of the protein, thus providing a mechanism whereby missense mutations result in loss of function of the PHEX protein. Endopeptidase activity of secreted and rescued PHEX proteins was assessed using a novel internally quenched fluorogenic peptide substrate.
{20:Gaucher et al. (2009)} analyzed the PHEX gene in 118 probands with hypophosphatemic rickets and identified mutations in 49 (87%) of 56 familial cases and 44 (73%) of 60 known sporadic cases. Of the 78 different mutations identified, 16 were missense mutations, which all occurred at residues that are highly conserved in mammals. Plotting all reported PHEX missense mutations on a 3D protein model revealed that missense mutations are primarily located in 2 regions in the inner part of the PHEX protein; similar plotting of nonsense mutations showed a random distribution. One patient with late-onset disease was found to have a mutation in an intronic region of PHEX, 2 bp away from the splice site consensus sequence, confirming that late-onset disease is part of the spectrum of X-linked dominant hypophosphatemic rickets.|* The 'Hyp' Mouse
{17:Eicher et al. (1976)} observed a mouse model for X-linked hypophosphatemia, designated Hyp. Hyp mice have bone changes resembling rickets, dwarfism, and high fractional excretion of phosphate ion.
By various transplantation experiments, {15:Ecarot-Charrier et al. (1988)} demonstrated an intrinsic defect in osteoblasts in the Hyp mouse. {3:Bell et al. (1988)} reported that primary cultures of renal epithelial cells from the Hyp mouse demonstrate a defect in phosphate transport and vitamin D metabolism, suggesting a defect intrinsic to the kidney. However, in cross-transplantation studies of kidneys in normal and Hyp mice, {33:Nesbitt et al. (1992)} found that the Hyp phenotype was neither transferred nor corrected by renal transplantation, suggesting that the kidney was not the target organ for the genetic abnormality. {33:Nesbitt et al. (1992)} postulated that the disorder in the mouse, and probably in the human, is the result of a humoral factor and is not an intrinsic renal abnormality. {33:Nesbitt et al. (1992)} suggested the presence of a unique hormonal effect that results in a blockade of, or failure to express, an essential gene function in a variety of cell types.
Parabiosis ({32:Meyer et al., 1989}) and renal transplantation ({33:Nesbitt et al., 1992}) experiments demonstrated that the renal defect in brush border membrane sodium-dependent phosphate transport in Hyp mice is not intrinsic to the kidney, but rather depends on a circulating humoral factor, which is not parathyroid hormone ({32:Meyer et al., 1989}), for its expression. In Hyp mice, {43:Tenenhouse et al. (1994)} demonstrated that the specific reduction in renal sodium-phosphate cotransport in brush border membranes could be ascribed to a proportionate decrease in the abundance of kidney NPT2 ({182309}) cotransporter mRNA and protein. However, the NPT2 gene is located on chromosome 5 and, hence, cannot be the site of the mutation primarily responsible for hereditary hypophosphatemia. {43:Tenenhouse et al. (1994)} suggested that the X-linked gene may encode the postulated circulating humoral factor that regulates the renal sodium-phosphate cotransporter.
{2:Beck et al. (1997)} discovered a large deletion in the 3-prime region of the Phex gene in the Hyp mouse.
{1:Baum et al. (2003)} demonstrated that Hyp mice have a 2-fold greater urinary prostaglandin E2 (PGE2) excretion than wildtype mice. To determine whether prostaglandins were involved in the pathogenesis of this disorder, Hyp and wildtype C57/B6 mice received intraperitoneal injections with vehicle or indomethacin and were studied approximately 12 hours after the last dose of indomethacin. In the Hyp mice, indomethacin decreased the fractional excretion of phosphate and increased serum phosphate. There was no effect of indomethacin in the wildtype mice. Indomethacin did not affect serum creatine or inulin clearance, demonstrating that the normalization of urinary phosphate excretion was not caused by changes in glomerular filtration rate. Indomethacin treatment increased renal brush border membrane vesicle NaPi2 protein abundance in Hyp mice to levels comparable to that of wildtype mice. {1:Baum et al. (2003)} concluded that there is dysregulation of renal prostaglandin metabolism in Hyp mice, and that indomethacin treatment normalizes the urinary excretion of phosphate by a direct tubular effect. These studies suggested that indomethacin may be an effective form of therapy in humans with X-linked hypophosphatemia.
{27:Lorenz-Depiereux et al. (2004)} studied 2 spontaneous mutations in the mouse Phex gene, Hyp-2J, a 7.3-kb deletion containing exon 15, and Hyp-Duk, a 30-kb deletion containing exons 13 and 14. Both mutations caused similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. Hyp-Duk males also exhibited background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology. Both Hyp-2J and Hyp-Duk males had thickened temporal bone surrounding the cochlea and a precipitate in the scala tympani, but only the hearing-impaired Hyp-Duk mice had degeneration of the organ of Corti and spiral ganglion. {27:Lorenz-Depiereux et al. (2004)} noted that XLH phenotypes could now be separated from non-XLH-related phenotypes.
During development and postnatal growth of the endochondral skeleton, proliferative chondrocytes differentiate into hypertrophic chondrocytes, which subsequently undergo apoptosis and are replaced by bone. {13:Donohue and Demay (2002)} found that mice with rickets due to ablation of the vitamin D receptor (VDR; {601769}) had expansion of hypertrophic chondrocytes due to impaired apoptosis of these cells. {38:Sabbagh et al. (2005)} showed that institution of a rescue diet that restored mineral ion homeostasis in Vdr-null mice prevented the development of rachitic changes, indicating that mineral ion abnormalities, not ablation of the Vdr gene, were the cause of impaired chondrocyte apoptosis. Similarly, Hyp mice with rickets also showed impaired apoptosis of hypertrophic chondrocytes, and the decreased apoptosis was correlated with hypophosphatemia. Wildtype mice rendered hypercalcemic and hypophosphatemic by dietary means also developed rickets. In vitro studies showed that the apoptosis was mediated by caspase-9 (CASP9; {602234}). {38:Sabbagh et al. (2005)} concluded that hypophosphatemia was the common mediator of rickets in these cases. The findings indicated that normal phosphorus levels are required for growth plate maturation and that circulating phosphate is a key regulator of hypertrophic chondrocyte apoptosis.
{44:Yuan et al. (2008)} generated mice with a global Phex knockout (Phex -/-) and mice with conditional osteocalcin-promoted Phex inactivation only in osteoblasts and osteocytes (OC-Phex -/-). The reduction in serum phosphorus levels and kidney cell membrane phosphate transport as compared to wildtype mice was similar among Hyp, Phex -/-, and OC-Phex -/- mice; all 3 mutant strains had increased bone production and serum FGF23 ({605370}) levels and decreased kidney membrane NPT2, and manifested comparable osteomalacia. {44:Yuan et al. (2008)} concluded that aberrant Phex function in osteoblasts and/or osteocytes alone is sufficient to underlie the Hyp phenotype.
The Gyro (Gy) Mouse
{28:Lyon et al. (1986)} identified a second type of X-linked dominant hypophosphatemia in the mouse in addition to the Hyp. The phenotype, called Gyro (Gy), is characterized by rickets/osteomalacia as in the Hyp mouse, but also shows circling behavior, inner ear abnormalities, sterility in hemizygous males, and a milder phenotype in heterozygous females. The Gy and Hyp mutations have similar expression in the renal tubule, but the Gy mutation has an additional effect on the inner ear. The Gy allele is expressed in the inner ear of some heterozygous mice, which show circling behavior. The authors found that Gy mapped close (crossover value 0.4-0.8%) to Hyp. Lowe syndrome ({309000}) is not a human counterpart of Gy because in that condition the transport defect is not limited to phosphorus; moreover, characteristic morphologic changes in the nephron observed in Lowe syndrome are not seen in the Gy mouse.
{35:Nesbitt et al. (1987)} found that PTH-dependent 1-alpha-hydroxylase (CYP27B1; {609506}) activity in the renal proximal convoluted tubule was abnormally regulated in the Hyp mouse, whereas calcitonin-dependent enzyme function in the proximal straight tubule was modulated normally.
In the search for a human equivalent of the Gy mutation, {4:Boneh et al. (1987)} measured hearing in 22 patients with X-linked hypophosphatemia; 5, including 2 mother/son pairs, had sensorineural hearing deficits due to cochlear dysfunction. The authors suggested that the disease in these persons may be the human counterpart of Gy.
{9:Davidai et al. (1990)} provided further information on the differences between the Hyp and Gy phenotypes in the mouse.
{8:Collins and Ghishan (1996)} found normal expression and location of the renal Na+/P(i) transporter NPT2 in Gy mice, suggesting that the molecular defect in the Gy mice is distinct from that in the Hyp mice, which show a decrease in transporter activity in the renal proximal tubules possibly related to decreased transcription ({6:Collins et al., 1995}).
In Gy mice, {42:Strom et al. (1997)} found a deletion of the first 3 exons and the promoter region of the PHEX, indicating that Hyp and Gy are allelic disorders. However, {30:Meyer et al. (1998)} found that the Gyro mouse has a partial deletion of both the Phex gene and the upstream spermine synthase gene ({300105}), making it a contiguous gene syndrome in that species. Gy is thus not as useful a model for human XLH as Hyp.|* The {25:HYP Consortium (1995)}, comprising 29 investigators in 5 institutions, isolated a candidate gene for X-linked hypophosphatemic rickets ({307800}) from the Xp22.1 region by positional cloning. The gene exhibited homology to a family of endopeptidase genes, members of which are involved in the degradation or activation of a variety of peptide hormones, including neutral endopeptidase (NEP; {120520}), endothelin-converting enzyme (ECE1; {600423}), and Kell blood group antigen ({613883}). Because of the homology and the function of the gene, the authors referred to it as PEX ('phosphate regulating gene with homologies to endopeptidases, on the X chromosome'). A partial PHEX sequence corresponding to 638 amino acids was presented. The PHEX cDNA was found to be evolutionarily conserved in primate, bovine, mouse, and hamster DNA, and possibly in chicken DNA.
{23:Guo and Quarles (1997)} isolated a human PHEX cDNA from a bone cDNA library. The deduced 749-amino acid protein has a molecular mass of 86.5 kD and shares 96% identity to the mouse sequence. The PHEX protein is predicted to have a 20-residue N-terminal cytoplasmic tail, a 27-residue transmembrane domain, and a 702-residue extracellular C-terminal region. The protein belongs to the type II integral membrane zinc-dependent endopeptidase family. PHEX transcripts were identified in human osteosarcoma-derived cells and in differentiated mouse osteoblasts, but not in immature mouse preosteoblasts, indicating stage-specific expression. {23:Guo and Quarles (1997)} suggested that PHEX may play a role in osteoblast-mediated bone mineralization.
{22:Grieff et al. (1997)} isolated human PHEX clones from an ovary cDNA library. The gene encodes a 749-amino acid polypeptide that is 96% identical to the murine Phex gene product and has significant homology to other members of the membrane-bound zinc metallopeptidase family. Northern blot analysis identified a 6.6-kb PHEX mRNA transcript at high levels in adult ovary and fetal lung and at lower levels in adult lung and fetal liver.
{14:Du et al. (1996)} reported the isolation and characterization of the complete open reading frame of the mouse Phex gene. The deduced 749-amino acid protein showed 95% identity to the available human PHEX sequence and significant homology to members of the membrane-bound metalloendopeptidase family. Northern blot analysis revealed a 6.6-kb mRNA transcript in bone and in cultured osteoblasts from normal mice; the transcript was not detectable in samples from the mutant 'Hyp' mouse but were detectable in Hyp bone by RT-PCR amplification. {2:Beck et al. (1997)} cloned mouse Phex and human PHEX cDNAs encoding part of the 5-prime untranslated region, the protein coding region, and the entire 3-prime untranslated region. Using RT-PCR and ribonuclease protection assays, they found that Phex/PHEX mRNA is expressed predominantly in human fetal and in adult mouse calvaria and long bone.|* The PEX nomenclature conflicts with the use of the same symbol for multiple peroxisomal proteins (peroxins) numbered 1 to 12 or more, e.g., PEX5 ({600414}). The gene symbol PHEX has much to recommend it ({12:Dixon et al., 1998}; {18:Filisetti et al., 1999}). | PMID:10439971,PMID:10874297,PMID:111782,PMID:11468271,PMID:11502821,PMID:12193585,PMID:12727977,PMID:12953100,PMID:15029877,PMID:1569185,PMID:15976027,PMID:16303832,PMID:18172553,PMID:18252791,PMID:188049,PMID:188828,PMID:19219621,PMID:2153705,PMID:2816498,PMID:2894375,PMID:3293983,PMID:3394683,PMID:3414685,PMID:3425609,PMID:3460077,PMID:3793922,PMID:3793922,PMID:6681616,PMID:7550339,PMID:7611412,PMID:8070635,PMID:8113402,PMID:8635692,PMID:879321,PMID:8812412,PMID:9063736,PMID:9063736,PMID:9070861,PMID:9077527,PMID:9106524,PMID:9199999,PMID:9545633,PMID:9768646,PMID:9768674 |
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OMIM | CYTOCHROME b(-245), BETA SUBUNIT; CYBB | CYTOCHROME b(558), BETA SUBUNIT;;
p91-PHOX;;
NADPH OXIDASE 2; NOX2;;
GP91-1, CYBB, CGD, AMCBX2, IMD34 | Immunodeficiency 34, mycobacteriosis, X-linked | X-linked recessive | X | {23:Jackson et al. (2004)} reported that activated mouse T cells deficient in either gp91-phox or p47-phox showed enhanced activation of Erk (see MAPK3; {601795}) and Mek (see MAP2K1; {176872}), diminished expression of phagocyte-type NADPH oxidase, and a relative increase in Th1-type cytokine secretion. They suggested that similar alterations may be found in patients with chronic granulomatous disease.
Dendritic cells (DCs) present antigens from pathogens or infected cells to CD8 (see {186910})-positive T cells after partial degradation of the antigens to 8- or 9-amino acid peptides, which is mediated by lysosomal proteases in an acidic environment. {37:Savina et al. (2006)} showed that DCs, but not macrophages, had an active machinery of phagosomal alkalinization that maintained the phagosomal pH between 7 and 7.5 for the first few hours after phagocytosis. Upon inactivation of the vacuolar ATPase (see {607028}), the phagosomal pH in DCs, but not macrophages, alkalinized strongly. Confocal microscopy demonstrated that NOX2 assembled on DC phagosomes in a gp91-phox subunit-dependent manner, and that reactive oxygen species were produced in a more sustained manner in immature DC phagosomes than in macrophage phagosomes. DCs obtained from mice lacking Nox2 due to deletion of gp91-phox displayed a rapid phagosomal acidification and increased antigen degradation, resulting in inefficient antigen crosspresentation. {37:Savina et al. (2006)} concluded that NOX2, a major player in innate immune responses in neutrophils, is also involved in adaptive immunity through its activity in DCs.
{33:Prosser et al. (2011)} reported that in heart cells, physiologic stretch rapidly activates reduced-form NOX2 to produce reactive oxygen species (ROS) in a process dependent on microtubules (X-ROS signaling). ROS production occurs in the sarcolemmal and t-tubule membranes where NOX2 is located and sensitizes nearby ryanodine receptors in the sarcoplasmic reticulum. This triggers a burst of Ca(2+) sparks, the elementary Ca(2+) release events in heart. Although this stretch-dependent 'tuning' of ryanodine receptors increases Ca(2+) signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca(2+) sparks to trigger arrhythmogenic Ca(2+) waves. In the mouse model of Duchenne muscular dystrophy ({310200}), hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca(2+) release from the sarcoplasmic reticulum. {33:Prosser et al. (2011)} concluded that X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca(2+) release in the heart and offers fresh therapeutic possibilities.|* By positional cloning, {36:Royer-Pokora et al. (1986)} identified the CYBB gene at Xp21.
{19:Gross (2014)} mapped the CYBB gene to chromosome Xp11.4 based on an alignment of the CYBB sequence (GenBank {GENBANK AF469769}) with the genomic sequence (GRCh38).
{3:Brockdorff et al. (1988)} used the cloned CYBB gene to map the mouse homolog to the X chromosome in an interspecific Mus domesticus/M. spretus cross.|* Cytochrome b(-245) is a heterodimer of the p91-phox beta polypeptide (CYBB) (phox for phagocyte oxidase) and a smaller p22-phox alpha polypeptide (CYBA; {608508}).
Cytochrome b(-245) is an essential component of phagocytic NADPH-oxidase, a membrane-bound enzyme complex that generates large quantities of microbicidal superoxide and other oxidants upon activation. Active NADPH oxidase also requires several cytosolic proteins, including p47-phox ({608512}), p67-phox ({233710}), p40-phox ({601488}), and a GTP-binding protein, either rac1 ({602048}) in macrophages or rac2 ({602049}) in neutrophils ({24:Leusen et al., 1994}). This cytochrome b has a very low midpoint potential of -245 mV and a characteristic spectrophotometric absorption band at 558 nm, and is also known as cytochrome b(558). The CYBB gene product has also been referred to as cgd91-phox ({38:Schapiro et al., 1991}).|* Enhanced redox stress and inflammation are associated with progression of amyotrophic lateral sclerosis (ALS; {105400}). {25:Marden et al. (2007)} evaluated the effects of Nox1 or Nox2 deletion on transgenic mice overexpressing human SOD1 ({147450}) with the ALS-associated gly93-to-ala mutation (G93A; {147450.0008}) by monitoring the onset and progression of disease using various indices. Disruption of either Nox1 or Nox2 significantly delayed progression of motor neuron disease in these mice. However, 50% survival rates were enhanced significantly more by Nox2 deletion than Nox1 deletion. Female mice lacking 1 copy of the X-chromosomal Nox1 or Nox2 genes also exhibited significantly increased survival rates, suggesting that in the setting of random X-inactivation, a 50% reduction in Nox1- or Nox2-expressing cells has a substantial therapeutic benefit in ALS mice. {25:Marden et al. (2007)} concluded that NOX1 and NOX2 contribute to the progression of ALS.|* In what may be the first example of 'reverse genetics,' later more appropriately termed 'positional cloning,' {36:Royer-Pokora et al. (1986)} cloned the gene that is abnormal in X-linked chronic granulomatous disease (CGD; {306400}) without reference to a specific protein. This was done by relying on the chromosomal map position of the gene and was, in effect, a byproduct of the chromosome walking experiments aimed at characterizing the DMD locus. From human leukemic cells treated with dimethylformamide, which induces the NADPH-oxidase system and other constituents of granulocytic differentiation, {36:Royer-Pokora et al. (1986)} isolated a cDNA that was subjected to subtractive hybridization with RNA from a cell line of a patient with deletion of the CGD/DMD complex in Xp21. The subtracted radiolabeled cDNA was hybridized to a Southern blot of Xp21 bacteriophage clones. Two overlapping clones (pERT 379) showed hybridization. The transcript of the gene was expressed in the phagocytic lineage of hematopoietic cells and was absent or structurally abnormal in 4 patients with CGD. The nucleotide sequence of cDNA clones predicted a polypeptide of at least 468 amino acids with no homology to previously described proteins. Specifically, cytochrome b was excluded. Although a consistent finding in X-linked CGD is absence of the heme spectrum derived from cytochrome b, the authors suggested that the deficiency may be secondary to the primary genetic abnormality.
{13:Dinauer et al. (1987)} raised antibodies to a synthetic peptide derived from the cDNA sequence of the putative CGD gene. Western blot analysis detected a neutrophil protein of relative molecular mass 90 kD that was absent in CGD patients. Antisera also reacted with the larger component of cytochrome b purified from neutrophil plasma membranes as a complex of glycosylated 90-kD and nonglycosylated 22-kD polypeptides. {13:Dinauer et al. (1987)} proposed that one of the critical roles of the CGD protein in vivo is to interact with the 22-kD polypeptide to form a functional cytochrome b complex.
Cytochrome b(-245) is a heterodimer composed of an alpha chain of relative molecular mass 23 kD and a beta chain of 76 to 82 kD. {40:Teahan et al. (1987)} purified the beta-chain protein of the cytochrome and sequenced 43 amino acids from the N terminus. Almost complete homology was obtained between this sequence and that of the complementary nucleotides 19-147 of the sequence of the CGD gene. {40:Teahan et al. (1987)} pointed to work indicating that cytochrome b(-245) is missing from the cells of CGD patients; neither the alpha nor the beta subunits are detectable in neutrophils from CGD patients. {32:Parkos et al. (1987)} demonstrated that the purified cytochrome b from human granulocyte plasma membrane is comprised of 2 polypeptides of relative molecular masses 91 kD and 22 kD, and noted that the 91-kD protein is affected in X-linked CGD.
{29:Orkin (1987)} stated that unraveling the genetic basis of X-linked CGD was dependent not only on gene cloning based on chromosomal map position and preparation of antisera directed to a known protein, but also on the existence of complementary biochemical data which identified the unknown product as a component of the cytochrome b complex.|* X-Linked Chronic Granulomatous Disease
In a patient with variant cytochrome b-positive X-linked CGD, {14:Dinauer et al. (1989)} identified a mutation in the CYBB gene ({300481.0001}). In 6 patients with X-linked CGD, both cytochrome b-negative and cytochrome b-positive forms, {2:Bolscher et al. (1991)} identified 6 different point mutations in the CYBB gene ({300481.0002}-{300481.0007}).
A remarkable family was described by {11:de Boer et al. (1998)} in which 2 brothers had CGD due to different mutations in the CYBB gene. One had a 3-kb deletion comprising exon 5 and the other a 3.5-kb deletion comprising exons 6 and 7. Sequence analysis of PCR-amplified genomic DNA showed that these deletions overlapped for 35 bp. Analysis by RFLP of genomic DNA from the mother's leukocytes showed her to be a carrier of both deletions in addition to the normal CYBB sequence, indicating triple somatic mosaicism. The presence of a normal CYBB gene in the mother was also proven by the finding of normal superoxide-generating neutrophils in addition to cells lacking this ability. Triple X syndrome was excluded. The finding suggested that the mutations resulted from an event in early embryogenesis in the mother, possibly involving a mechanism such as sister chromatid exchange.
{27:Noack et al. (2001)} described a second case of somatic triple mosaicism, the mutation in the patient being the insertion of 12 bp in intron 11, accompanied by the deletion of exon 12. The grandmother of this patient was chimeric, carrying a normal allele, the patient's allele, and an allele with a 4-nucleotide insertion at a site adjacent to the patient's insertion, in combination with a 1.5-kb deletion within intron 11. The patient's mother carried a normal allele and the patient's allele. {27:Noack et al. (2001)} proposed that an initial mutational event during the grandmother's embryogenesis had undergone unsuccessful DNA repair and resulted in 2 aberrant alleles, 1 of which had been inherited by the patient and his mother.
{34:Rae et al. (1998)} identified the mutations in the CYBB gene responsible for X-linked CGD in 131 consecutive independent kindreds. Screening by SSCP analysis identified mutations in 124 of the kindreds, and sequencing of all exons and intron boundary regions revealed the other 7 mutations. They detected 103 different specific mutations; no single mutation appeared in more than 7 independent kindreds. The types of mutations included large and small deletions (11%), frameshifts (24%), nonsense mutations (23%), missense mutations (23%), splice region mutations (17%), and regulatory-region mutations (2%). The distribution of mutations within the CYBB gene exhibited great heterogeneity, with no apparent mutation hotspots. Evaluation of 87 available mothers revealed X-linked carrier status in all but 10. The heterogeneity of mutations and the lack of any predominant genotype indicate that the disease represents many different mutational events, without a founder effect, as is expected for a disorder with a previously lethal phenotype.
Immunodeficiency-34
In 7 males from 2 kindreds with X-linked familial atypical mycobacteriosis (IMD34; {300645}), {5:Bustamante et al. (2011)} identified missense mutations in the CYBB gene ({300481.0022} and {300481.0023}). All clinically affected males in both kindreds were hemizygous for the mutated allele, whereas other maternally related healthy males tested were not. All 11 obligate female carriers tested in the 2 kindreds were heterozygous for the mutated allele. {5:Bustamante et al. (2011)} found that all affected males, as well as other family members, had normal NADPH oxidase activity in circulating neutrophils and monocytes, unlike individuals with CGD or variant CGD. However, in vitro differentiation of monocytes to macrophages in the presence of MCSF (CSF1; {120420}) revealed that NADPH oxidase activity was impaired in patient macrophages, and the ability to control the growth of BCG was reduced. Impairment of NADPH oxidase activity was also demonstrable in patient B-cell lines. Immunoblot analysis showed reduced expression of CYBB in patient neutrophils and monocytes, with a much greater reduction in monocyte-derived macrophages. Immunohistochemistry showed impaired production of CYBB in patient lymph node macrophages. {5:Bustamante et al. (2011)} concluded that the CYBB mutations in these 7 adult patients, who had no history of other granulomatous or infectious diseases, resulted in dysfunction of macrophages, but not in dysfunction of granulocytes or monocytes. | PMID:10828042,PMID:10828042,PMID:10914676,PMID:10980575,PMID:11435314,PMID:11511930,PMID:11566256,PMID:11700292,PMID:11997083,PMID:12094329,PMID:1347621,PMID:14258653,PMID:1438069,PMID:15258578,PMID:15308575,PMID:15338276,PMID:16839887,PMID:1710153,PMID:1719419,PMID:17293536,PMID:17853944,PMID:21903813,PMID:2425263,PMID:2523713,PMID:2556453,PMID:2838754,PMID:3197451,PMID:3305576,PMID:3600768,PMID:3600769,PMID:8182143,PMID:8634410,PMID:8900212,PMID:8916969,PMID:9414292,PMID:9585602,PMID:9856476 |
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OMIM | CYTOCHROME b(-245), BETA SUBUNIT; CYBB | CYTOCHROME b(558), BETA SUBUNIT;;
p91-PHOX;;
NADPH OXIDASE 2; NOX2;;
GP91-1, CYBB, CGD, AMCBX2, IMD34 | Chronic granulomatous disease, X-linked | X-linked recessive | X | {23:Jackson et al. (2004)} reported that activated mouse T cells deficient in either gp91-phox or p47-phox showed enhanced activation of Erk (see MAPK3; {601795}) and Mek (see MAP2K1; {176872}), diminished expression of phagocyte-type NADPH oxidase, and a relative increase in Th1-type cytokine secretion. They suggested that similar alterations may be found in patients with chronic granulomatous disease.
Dendritic cells (DCs) present antigens from pathogens or infected cells to CD8 (see {186910})-positive T cells after partial degradation of the antigens to 8- or 9-amino acid peptides, which is mediated by lysosomal proteases in an acidic environment. {37:Savina et al. (2006)} showed that DCs, but not macrophages, had an active machinery of phagosomal alkalinization that maintained the phagosomal pH between 7 and 7.5 for the first few hours after phagocytosis. Upon inactivation of the vacuolar ATPase (see {607028}), the phagosomal pH in DCs, but not macrophages, alkalinized strongly. Confocal microscopy demonstrated that NOX2 assembled on DC phagosomes in a gp91-phox subunit-dependent manner, and that reactive oxygen species were produced in a more sustained manner in immature DC phagosomes than in macrophage phagosomes. DCs obtained from mice lacking Nox2 due to deletion of gp91-phox displayed a rapid phagosomal acidification and increased antigen degradation, resulting in inefficient antigen crosspresentation. {37:Savina et al. (2006)} concluded that NOX2, a major player in innate immune responses in neutrophils, is also involved in adaptive immunity through its activity in DCs.
{33:Prosser et al. (2011)} reported that in heart cells, physiologic stretch rapidly activates reduced-form NOX2 to produce reactive oxygen species (ROS) in a process dependent on microtubules (X-ROS signaling). ROS production occurs in the sarcolemmal and t-tubule membranes where NOX2 is located and sensitizes nearby ryanodine receptors in the sarcoplasmic reticulum. This triggers a burst of Ca(2+) sparks, the elementary Ca(2+) release events in heart. Although this stretch-dependent 'tuning' of ryanodine receptors increases Ca(2+) signaling sensitivity in healthy cardiomyocytes, in disease it enables Ca(2+) sparks to trigger arrhythmogenic Ca(2+) waves. In the mouse model of Duchenne muscular dystrophy ({310200}), hyperactive X-ROS signaling contributes to cardiomyopathy through aberrant Ca(2+) release from the sarcoplasmic reticulum. {33:Prosser et al. (2011)} concluded that X-ROS signaling thus provides a mechanistic explanation for the mechanotransduction of Ca(2+) release in the heart and offers fresh therapeutic possibilities.|* By positional cloning, {36:Royer-Pokora et al. (1986)} identified the CYBB gene at Xp21.
{19:Gross (2014)} mapped the CYBB gene to chromosome Xp11.4 based on an alignment of the CYBB sequence (GenBank {GENBANK AF469769}) with the genomic sequence (GRCh38).
{3:Brockdorff et al. (1988)} used the cloned CYBB gene to map the mouse homolog to the X chromosome in an interspecific Mus domesticus/M. spretus cross.|* Cytochrome b(-245) is a heterodimer of the p91-phox beta polypeptide (CYBB) (phox for phagocyte oxidase) and a smaller p22-phox alpha polypeptide (CYBA; {608508}).
Cytochrome b(-245) is an essential component of phagocytic NADPH-oxidase, a membrane-bound enzyme complex that generates large quantities of microbicidal superoxide and other oxidants upon activation. Active NADPH oxidase also requires several cytosolic proteins, including p47-phox ({608512}), p67-phox ({233710}), p40-phox ({601488}), and a GTP-binding protein, either rac1 ({602048}) in macrophages or rac2 ({602049}) in neutrophils ({24:Leusen et al., 1994}). This cytochrome b has a very low midpoint potential of -245 mV and a characteristic spectrophotometric absorption band at 558 nm, and is also known as cytochrome b(558). The CYBB gene product has also been referred to as cgd91-phox ({38:Schapiro et al., 1991}).|* Enhanced redox stress and inflammation are associated with progression of amyotrophic lateral sclerosis (ALS; {105400}). {25:Marden et al. (2007)} evaluated the effects of Nox1 or Nox2 deletion on transgenic mice overexpressing human SOD1 ({147450}) with the ALS-associated gly93-to-ala mutation (G93A; {147450.0008}) by monitoring the onset and progression of disease using various indices. Disruption of either Nox1 or Nox2 significantly delayed progression of motor neuron disease in these mice. However, 50% survival rates were enhanced significantly more by Nox2 deletion than Nox1 deletion. Female mice lacking 1 copy of the X-chromosomal Nox1 or Nox2 genes also exhibited significantly increased survival rates, suggesting that in the setting of random X-inactivation, a 50% reduction in Nox1- or Nox2-expressing cells has a substantial therapeutic benefit in ALS mice. {25:Marden et al. (2007)} concluded that NOX1 and NOX2 contribute to the progression of ALS.|* In what may be the first example of 'reverse genetics,' later more appropriately termed 'positional cloning,' {36:Royer-Pokora et al. (1986)} cloned the gene that is abnormal in X-linked chronic granulomatous disease (CGD; {306400}) without reference to a specific protein. This was done by relying on the chromosomal map position of the gene and was, in effect, a byproduct of the chromosome walking experiments aimed at characterizing the DMD locus. From human leukemic cells treated with dimethylformamide, which induces the NADPH-oxidase system and other constituents of granulocytic differentiation, {36:Royer-Pokora et al. (1986)} isolated a cDNA that was subjected to subtractive hybridization with RNA from a cell line of a patient with deletion of the CGD/DMD complex in Xp21. The subtracted radiolabeled cDNA was hybridized to a Southern blot of Xp21 bacteriophage clones. Two overlapping clones (pERT 379) showed hybridization. The transcript of the gene was expressed in the phagocytic lineage of hematopoietic cells and was absent or structurally abnormal in 4 patients with CGD. The nucleotide sequence of cDNA clones predicted a polypeptide of at least 468 amino acids with no homology to previously described proteins. Specifically, cytochrome b was excluded. Although a consistent finding in X-linked CGD is absence of the heme spectrum derived from cytochrome b, the authors suggested that the deficiency may be secondary to the primary genetic abnormality.
{13:Dinauer et al. (1987)} raised antibodies to a synthetic peptide derived from the cDNA sequence of the putative CGD gene. Western blot analysis detected a neutrophil protein of relative molecular mass 90 kD that was absent in CGD patients. Antisera also reacted with the larger component of cytochrome b purified from neutrophil plasma membranes as a complex of glycosylated 90-kD and nonglycosylated 22-kD polypeptides. {13:Dinauer et al. (1987)} proposed that one of the critical roles of the CGD protein in vivo is to interact with the 22-kD polypeptide to form a functional cytochrome b complex.
Cytochrome b(-245) is a heterodimer composed of an alpha chain of relative molecular mass 23 kD and a beta chain of 76 to 82 kD. {40:Teahan et al. (1987)} purified the beta-chain protein of the cytochrome and sequenced 43 amino acids from the N terminus. Almost complete homology was obtained between this sequence and that of the complementary nucleotides 19-147 of the sequence of the CGD gene. {40:Teahan et al. (1987)} pointed to work indicating that cytochrome b(-245) is missing from the cells of CGD patients; neither the alpha nor the beta subunits are detectable in neutrophils from CGD patients. {32:Parkos et al. (1987)} demonstrated that the purified cytochrome b from human granulocyte plasma membrane is comprised of 2 polypeptides of relative molecular masses 91 kD and 22 kD, and noted that the 91-kD protein is affected in X-linked CGD.
{29:Orkin (1987)} stated that unraveling the genetic basis of X-linked CGD was dependent not only on gene cloning based on chromosomal map position and preparation of antisera directed to a known protein, but also on the existence of complementary biochemical data which identified the unknown product as a component of the cytochrome b complex.|* X-Linked Chronic Granulomatous Disease
In a patient with variant cytochrome b-positive X-linked CGD, {14:Dinauer et al. (1989)} identified a mutation in the CYBB gene ({300481.0001}). In 6 patients with X-linked CGD, both cytochrome b-negative and cytochrome b-positive forms, {2:Bolscher et al. (1991)} identified 6 different point mutations in the CYBB gene ({300481.0002}-{300481.0007}).
A remarkable family was described by {11:de Boer et al. (1998)} in which 2 brothers had CGD due to different mutations in the CYBB gene. One had a 3-kb deletion comprising exon 5 and the other a 3.5-kb deletion comprising exons 6 and 7. Sequence analysis of PCR-amplified genomic DNA showed that these deletions overlapped for 35 bp. Analysis by RFLP of genomic DNA from the mother's leukocytes showed her to be a carrier of both deletions in addition to the normal CYBB sequence, indicating triple somatic mosaicism. The presence of a normal CYBB gene in the mother was also proven by the finding of normal superoxide-generating neutrophils in addition to cells lacking this ability. Triple X syndrome was excluded. The finding suggested that the mutations resulted from an event in early embryogenesis in the mother, possibly involving a mechanism such as sister chromatid exchange.
{27:Noack et al. (2001)} described a second case of somatic triple mosaicism, the mutation in the patient being the insertion of 12 bp in intron 11, accompanied by the deletion of exon 12. The grandmother of this patient was chimeric, carrying a normal allele, the patient's allele, and an allele with a 4-nucleotide insertion at a site adjacent to the patient's insertion, in combination with a 1.5-kb deletion within intron 11. The patient's mother carried a normal allele and the patient's allele. {27:Noack et al. (2001)} proposed that an initial mutational event during the grandmother's embryogenesis had undergone unsuccessful DNA repair and resulted in 2 aberrant alleles, 1 of which had been inherited by the patient and his mother.
{34:Rae et al. (1998)} identified the mutations in the CYBB gene responsible for X-linked CGD in 131 consecutive independent kindreds. Screening by SSCP analysis identified mutations in 124 of the kindreds, and sequencing of all exons and intron boundary regions revealed the other 7 mutations. They detected 103 different specific mutations; no single mutation appeared in more than 7 independent kindreds. The types of mutations included large and small deletions (11%), frameshifts (24%), nonsense mutations (23%), missense mutations (23%), splice region mutations (17%), and regulatory-region mutations (2%). The distribution of mutations within the CYBB gene exhibited great heterogeneity, with no apparent mutation hotspots. Evaluation of 87 available mothers revealed X-linked carrier status in all but 10. The heterogeneity of mutations and the lack of any predominant genotype indicate that the disease represents many different mutational events, without a founder effect, as is expected for a disorder with a previously lethal phenotype.
Immunodeficiency-34
In 7 males from 2 kindreds with X-linked familial atypical mycobacteriosis (IMD34; {300645}), {5:Bustamante et al. (2011)} identified missense mutations in the CYBB gene ({300481.0022} and {300481.0023}). All clinically affected males in both kindreds were hemizygous for the mutated allele, whereas other maternally related healthy males tested were not. All 11 obligate female carriers tested in the 2 kindreds were heterozygous for the mutated allele. {5:Bustamante et al. (2011)} found that all affected males, as well as other family members, had normal NADPH oxidase activity in circulating neutrophils and monocytes, unlike individuals with CGD or variant CGD. However, in vitro differentiation of monocytes to macrophages in the presence of MCSF (CSF1; {120420}) revealed that NADPH oxidase activity was impaired in patient macrophages, and the ability to control the growth of BCG was reduced. Impairment of NADPH oxidase activity was also demonstrable in patient B-cell lines. Immunoblot analysis showed reduced expression of CYBB in patient neutrophils and monocytes, with a much greater reduction in monocyte-derived macrophages. Immunohistochemistry showed impaired production of CYBB in patient lymph node macrophages. {5:Bustamante et al. (2011)} concluded that the CYBB mutations in these 7 adult patients, who had no history of other granulomatous or infectious diseases, resulted in dysfunction of macrophages, but not in dysfunction of granulocytes or monocytes. | PMID:10828042,PMID:10828042,PMID:10914676,PMID:10980575,PMID:11435314,PMID:11511930,PMID:11566256,PMID:11700292,PMID:11997083,PMID:12094329,PMID:1347621,PMID:14258653,PMID:1438069,PMID:15258578,PMID:15308575,PMID:15338276,PMID:16839887,PMID:1710153,PMID:1719419,PMID:17293536,PMID:17853944,PMID:21903813,PMID:2425263,PMID:2523713,PMID:2556453,PMID:2838754,PMID:3197451,PMID:3305576,PMID:3600768,PMID:3600769,PMID:8182143,PMID:8634410,PMID:8900212,PMID:8916969,PMID:9414292,PMID:9585602,PMID:9856476 |
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OMIM | CHLORIDE INTRACELLULAR CHANNEL 2; CLIC2 | XAP121, CLIC2, XAP121, MRXS32 | Mental retardation, X-linked, syndromic 32 | X-linked recessive | X | {1:Board et al. (2004)} demonstrated that CLIC2 is a strong inhibitor of the cardiac ryanodine receptor (RYR2) calcium release channels in both lipid bilayers and in cardiac sarcoplasmic reticulum vesicles, suggesting that it contributes to intracellular calcium homeostasis by regulating its release from internal stores in the cell.
{2:Dulhunty et al. (2005)} demonstrated that CLIC2 reduces activation of the RYR2 channel by its primary endogenous ligands ATP and calcium. When CLIC2 was added to the cytoplasmic side of RYR2 channels in lipid bilayers, RYR2 activity was depressed in a reversible, voltage-independent manner. The authors concluded that CLIC2 may act physiologically as a cytosolic inhibitor of RYR2 channels during diastole and during stress.|* {3:Heiss and Poustka (1997)} found that the CLIC2 gene contains 6 exons.|* {4:Rogner et al. (1996)} identified the CLIC2 gene on chromosome Xq28.|* As part of an effort to produce a transcript map of the Xq28 chromosomal region, {4:Rogner et al. (1996)} characterized a cDNA that they designated XAP121, or CLIC2. {3:Heiss and Poustka (1997)} reported that the predicted 243-amino acid CLIC2 protein shares 60% identity with the CLIC1 protein, a nuclear chloride channel. Using RT-PCR, {4:Rogner et al. (1996)} found that CLIC2 is expressed in fetal liver and adult skeletal muscle. No signal was detected on Northern blots.
{1:Board et al. (2004)} stated that the predicted CLIC2 protein has a molecular mass of 27.8 kD. The protein sequence showed 58.8% identity to CLIC1 and 18.6% identity to GSTO1. Northern blot analysis detected 2 abundant mRNA species of 1.45 and 2.37 kb, and a third less abundant species of 0.8 kb. The 2 larger mRNA transcripts were widely distributed in human tissues, with highest expression in lung and spleen and lesser expression in heart, liver, and skeletal muscle.
Using RT-PCR, {5:Takano et al. (2012)} found expression of the CLIC2 gene in all fetal tissues, including brain.|* In 2 brothers with syndromic X-linked mental retardation-32 (MRXS32; {300886}), {5:Takano et al. (2012)} identified a hemizygous mutation in the CLIC2 gene (H101Q; {300138.0001}). The mutation was inherited from the mother who had mild learning disabilities. The mutant protein had increased thermal stability compared to wildtype, and caused an increase in both the skeletal RYR1 ({180901}) and cardiac RYR2 channels being in the open probability states, which was a reversal of the effect of wildtype CLIC2. Three-dimensional predictions indicated that the H101Q mutation affected the binding affinity to RYR channels, resulting in stronger and more stable binding compared to wildtype. Overall, the data suggested that mutant CLIC2 would stimulate the release of calcium by keeping the RYR channels in the open state, resulting in overly active RYR2 in heart muscle with excess potential firing in those cells. The patients had profound mental retardation and adult-onset cardiomegaly, but did not have apparent skeletal muscle abnormalities.|* The CLIC2 gene encodes a protein that belongs to a class of soluble and membrane-bound proteins named because the first members of this family formed intracellular chloride channels. The CLIC2 protein is structurally similar to CLIC1 ({602872}) and to a form of glutathione transferase (GSTO1; {605482}), but has no transferase activity. CLIC2 functions as a regulator of calcium homeostasis in cardiac myocytes via interaction with the cardiac ryanodine receptor (RYR2; {180902}) (summary by {1:Board et al., 2004}). | PMID:15147738,PMID:15916532,PMID:22814392,PMID:8908511,PMID:9339381 |
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OMIM | PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1 | | Phosphoribosylpyrophosphate synthetase superactivity | X-linked recessive | X | {10:De Brouwer et al. (2010)} provided a review of the clinical and molecular features of the 4 distinct syndromes caused by mutation in the PRPS1 gene: PRPS1 superactivity ({300661}), X-linked Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), Arts syndrome ({301835}), and isolated X-linked sensorineural deafness ({304500}). The neurologic phenotype in all 4 PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in 2 Australian brothers with Arts syndrome revealed some improvement of their condition, suggesting that SAM supplementation could potentially alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides.
Phosphoribosylpyrophosphate Synthetase Superactivity
In patients with phosphoribosylpyrophosphate synthetase superactivity ({300661}), {21,20:Roessler et al. (1991, 1993)} and {6:Becker et al. (1995)} identified mutations in the PRPS1 gene ({311850.0001}-{311850.0008}). All patients except 1 had hyperuricemia, neurodevelopmental abnormalities, and sensorineural deafness; the other patient had only hyperuricemia and gout. Functional expression studies of all mutations showed that enzyme overactivity was due to alteration of allosteric feedback mechanisms.
Charcot-Marie-Tooth Disease, X-linked Recessive, 5
In affected males with X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), {13:Kim et al. (2007)} identified mutations in the PRPS1 gene ({311850.0009}; {311850.0010}). The phenotype includes peripheral neuropathy, sensorineural deafness, and visual impairment. {13:Kim et al. (2007)} used a positional cloning technique and evaluation of candidate genes known to be expressed in the cochlea to identify the PRPS1 gene for study. The mutations were shown to result in decreased enzyme activity; none of the affected individuals had increased uric acid or gout. {13:Kim et al. (2007)} noted that both PRPS1 superactivity and CMT5X phenotypes share neurologic features.
Arts Syndrome
Arts syndrome ({301835}) is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Using oligonucleotide microarray expression profiling of fibroblasts from 2 probands in a Dutch family with Arts syndrome, {11:de Brouwer et al. (2007)} found reduced expression levels of PRPS1. Sequencing of PRPS1 led to the identification of 2 different missense mutations: L152P ({311850.0011}) in the Dutch family and Q133P ({311850.0012}) in the Australian family. Both mutations resulted in a loss of PRPS1 activity, as was shown in silico by molecular modeling and was shown in vitro by enzyme assays in erythrocytes and fibroblasts from patients. This was in contrast to the gain-of-function mutations in PRPS1 identified in PRPS-related gout. The loss-of-function mutations of PRPS1 probably result in impaired purine biosynthesis, which was supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. {11:De Brouwer et al. (2007)} suggested that treatment with S-adenosylmethionine (SAM) theoretically could have therapeutic efficacy to replenish low levels of purine, and a clinical trial involving the 2 affected Australian brothers was underway. {10:De Brouwer et al. (2010)} reported preliminary results of the 2 Australian brothers with Arts syndrome.
X-linked Deafness 1
In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss (NSHL) mapping to the DNF2 locus (DFNX1; {304500}) on chromosome Xq22, {15:Liu et al. (2010)} analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; {311850.0013}) that cosegregated with the phenotype. Analysis of the PRPS1 gene in a British American DNF2 family, previously reported by {23:Tyson et al. (1996)}, revealed a different missense mutation (A87T; {311850.0014}); missense mutations were also detected in DFN2 families previously reported by {16:Manolis et al. (1999)} and {9:Cui et al. (2004)} ({311850.0015} and {311850.0016}, respectively). {15:Liu et al. (2010)} stated that none of the mutations were predicted to result in a major structural change in the PRPS1 protein, which might explain why the disease phenotype was limited to NSHL.|* {19:Roessler et al. (1990)} isolated a partial clone corresponding to the PRPS1 gene from a human lymphoblast cDNA library. The deduced PRPS1 protein has 318 amino acids and shares 95% amino acid homology with PRPS2. {3:Becker et al. (1990)} also cloned the PRPS1 gene and detected a 2.3-kb mRNA transcript.
By Northern blot analysis using rat Prps1 as probe, {22:Taira et al. (1989)} detected a 2.3-kb transcript in human adipose tissue, testis, and placenta and in 2 human cell lines.
{13:Kim et al. (2007)} demonstrated that the PRPS1 amino acid sequence shows an exceptionally high degree of conservation, with homologies greater than 95% across different species from zebrafish to human.|* {24:Wada et al. (1974)} and {12:Iinuma et al. (1975)} reported a Japanese infant with mental retardation, hypouricemia, megaloblastic changes in the bone marrow, and orotic aciduria associated with erythrocyte PRPS deficiency. Hypsarrhythmia was first observed at 10 months of age and markedly improved with ACTH therapy concomitant with an increase in red cell PRPS activity. However, studies in fibroblasts from this patient did not confirm enzyme deficiency ({2:Becker, 2001}).|* By the Goss-Harris method, {7:Becker et al. (1978)} concluded that the order of loci on chromosome Xq is G6PD ({305900})--HPRT1 ({308000})--PRPS1--alpha-GAL (GLA; {300644})--PGK1 ({311800})--centromere. {8:Becker et al. (1979)} assigned the PRPS1 locus to a position between the GLA and HPRT1 loci, particularly close to the latter, and discussed the functional significance of the proximity of the genes for their biochemically related functions.
{3:Becker et al. (1990)} mapped PRPS1 to Xq22-q24 by a combination of in situ hybridization and study of human/rodent somatic cell hybrids.
Pseudogene
By in situ chromosomal hybridization, {3:Becker et al. (1990)} identified a PRPS1-related gene or pseudogene (PRPS1L2) on chromosome 9q33-q34.|* Phosphoribosylpyrophosphate synthetase (PRPS; {EC 2.7.6.1}) catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis ({19:Roessler et al., 1990}). Three PRPS genes have been identified: the widely expressed PRPS1 and PRPS2 ({311860}) genes, which map to chromosome Xq22-q24 and Xp22, respectively, and PRPS3 (PRPS1L1; {611566}), which maps to chromosome 7 and appears to be transcribed only in testis ({2:Becker, 2001}).|* The PRPS1 gene spans over 30 kb and contains 7 exons ({2:Becker, 2001}). | PMID:10503584,PMID:15240907,PMID:168665,PMID:171280,PMID:17701896,PMID:17701900,PMID:1962753,PMID:20021999,PMID:20380929,PMID:2155397,PMID:217337,PMID:218284,PMID:22246954,PMID:2423135,PMID:24285972,PMID:2537655,PMID:4373874,PMID:6243137,PMID:7593598,PMID:8253776,PMID:8498830,PMID:8968763 |
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OMIM | PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1 | | Gout, PRPS-related | X-linked recessive | X | {10:De Brouwer et al. (2010)} provided a review of the clinical and molecular features of the 4 distinct syndromes caused by mutation in the PRPS1 gene: PRPS1 superactivity ({300661}), X-linked Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), Arts syndrome ({301835}), and isolated X-linked sensorineural deafness ({304500}). The neurologic phenotype in all 4 PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in 2 Australian brothers with Arts syndrome revealed some improvement of their condition, suggesting that SAM supplementation could potentially alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides.
Phosphoribosylpyrophosphate Synthetase Superactivity
In patients with phosphoribosylpyrophosphate synthetase superactivity ({300661}), {21,20:Roessler et al. (1991, 1993)} and {6:Becker et al. (1995)} identified mutations in the PRPS1 gene ({311850.0001}-{311850.0008}). All patients except 1 had hyperuricemia, neurodevelopmental abnormalities, and sensorineural deafness; the other patient had only hyperuricemia and gout. Functional expression studies of all mutations showed that enzyme overactivity was due to alteration of allosteric feedback mechanisms.
Charcot-Marie-Tooth Disease, X-linked Recessive, 5
In affected males with X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), {13:Kim et al. (2007)} identified mutations in the PRPS1 gene ({311850.0009}; {311850.0010}). The phenotype includes peripheral neuropathy, sensorineural deafness, and visual impairment. {13:Kim et al. (2007)} used a positional cloning technique and evaluation of candidate genes known to be expressed in the cochlea to identify the PRPS1 gene for study. The mutations were shown to result in decreased enzyme activity; none of the affected individuals had increased uric acid or gout. {13:Kim et al. (2007)} noted that both PRPS1 superactivity and CMT5X phenotypes share neurologic features.
Arts Syndrome
Arts syndrome ({301835}) is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Using oligonucleotide microarray expression profiling of fibroblasts from 2 probands in a Dutch family with Arts syndrome, {11:de Brouwer et al. (2007)} found reduced expression levels of PRPS1. Sequencing of PRPS1 led to the identification of 2 different missense mutations: L152P ({311850.0011}) in the Dutch family and Q133P ({311850.0012}) in the Australian family. Both mutations resulted in a loss of PRPS1 activity, as was shown in silico by molecular modeling and was shown in vitro by enzyme assays in erythrocytes and fibroblasts from patients. This was in contrast to the gain-of-function mutations in PRPS1 identified in PRPS-related gout. The loss-of-function mutations of PRPS1 probably result in impaired purine biosynthesis, which was supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. {11:De Brouwer et al. (2007)} suggested that treatment with S-adenosylmethionine (SAM) theoretically could have therapeutic efficacy to replenish low levels of purine, and a clinical trial involving the 2 affected Australian brothers was underway. {10:De Brouwer et al. (2010)} reported preliminary results of the 2 Australian brothers with Arts syndrome.
X-linked Deafness 1
In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss (NSHL) mapping to the DNF2 locus (DFNX1; {304500}) on chromosome Xq22, {15:Liu et al. (2010)} analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; {311850.0013}) that cosegregated with the phenotype. Analysis of the PRPS1 gene in a British American DNF2 family, previously reported by {23:Tyson et al. (1996)}, revealed a different missense mutation (A87T; {311850.0014}); missense mutations were also detected in DFN2 families previously reported by {16:Manolis et al. (1999)} and {9:Cui et al. (2004)} ({311850.0015} and {311850.0016}, respectively). {15:Liu et al. (2010)} stated that none of the mutations were predicted to result in a major structural change in the PRPS1 protein, which might explain why the disease phenotype was limited to NSHL.|* {19:Roessler et al. (1990)} isolated a partial clone corresponding to the PRPS1 gene from a human lymphoblast cDNA library. The deduced PRPS1 protein has 318 amino acids and shares 95% amino acid homology with PRPS2. {3:Becker et al. (1990)} also cloned the PRPS1 gene and detected a 2.3-kb mRNA transcript.
By Northern blot analysis using rat Prps1 as probe, {22:Taira et al. (1989)} detected a 2.3-kb transcript in human adipose tissue, testis, and placenta and in 2 human cell lines.
{13:Kim et al. (2007)} demonstrated that the PRPS1 amino acid sequence shows an exceptionally high degree of conservation, with homologies greater than 95% across different species from zebrafish to human.|* {24:Wada et al. (1974)} and {12:Iinuma et al. (1975)} reported a Japanese infant with mental retardation, hypouricemia, megaloblastic changes in the bone marrow, and orotic aciduria associated with erythrocyte PRPS deficiency. Hypsarrhythmia was first observed at 10 months of age and markedly improved with ACTH therapy concomitant with an increase in red cell PRPS activity. However, studies in fibroblasts from this patient did not confirm enzyme deficiency ({2:Becker, 2001}).|* By the Goss-Harris method, {7:Becker et al. (1978)} concluded that the order of loci on chromosome Xq is G6PD ({305900})--HPRT1 ({308000})--PRPS1--alpha-GAL (GLA; {300644})--PGK1 ({311800})--centromere. {8:Becker et al. (1979)} assigned the PRPS1 locus to a position between the GLA and HPRT1 loci, particularly close to the latter, and discussed the functional significance of the proximity of the genes for their biochemically related functions.
{3:Becker et al. (1990)} mapped PRPS1 to Xq22-q24 by a combination of in situ hybridization and study of human/rodent somatic cell hybrids.
Pseudogene
By in situ chromosomal hybridization, {3:Becker et al. (1990)} identified a PRPS1-related gene or pseudogene (PRPS1L2) on chromosome 9q33-q34.|* Phosphoribosylpyrophosphate synthetase (PRPS; {EC 2.7.6.1}) catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis ({19:Roessler et al., 1990}). Three PRPS genes have been identified: the widely expressed PRPS1 and PRPS2 ({311860}) genes, which map to chromosome Xq22-q24 and Xp22, respectively, and PRPS3 (PRPS1L1; {611566}), which maps to chromosome 7 and appears to be transcribed only in testis ({2:Becker, 2001}).|* The PRPS1 gene spans over 30 kb and contains 7 exons ({2:Becker, 2001}). | PMID:10503584,PMID:15240907,PMID:168665,PMID:171280,PMID:17701896,PMID:17701900,PMID:1962753,PMID:20021999,PMID:20380929,PMID:2155397,PMID:217337,PMID:218284,PMID:22246954,PMID:2423135,PMID:24285972,PMID:2537655,PMID:4373874,PMID:6243137,PMID:7593598,PMID:8253776,PMID:8498830,PMID:8968763 |
|
OMIM | PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1 | | Arts syndrome | X-linked recessive | X | {10:De Brouwer et al. (2010)} provided a review of the clinical and molecular features of the 4 distinct syndromes caused by mutation in the PRPS1 gene: PRPS1 superactivity ({300661}), X-linked Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), Arts syndrome ({301835}), and isolated X-linked sensorineural deafness ({304500}). The neurologic phenotype in all 4 PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in 2 Australian brothers with Arts syndrome revealed some improvement of their condition, suggesting that SAM supplementation could potentially alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides.
Phosphoribosylpyrophosphate Synthetase Superactivity
In patients with phosphoribosylpyrophosphate synthetase superactivity ({300661}), {21,20:Roessler et al. (1991, 1993)} and {6:Becker et al. (1995)} identified mutations in the PRPS1 gene ({311850.0001}-{311850.0008}). All patients except 1 had hyperuricemia, neurodevelopmental abnormalities, and sensorineural deafness; the other patient had only hyperuricemia and gout. Functional expression studies of all mutations showed that enzyme overactivity was due to alteration of allosteric feedback mechanisms.
Charcot-Marie-Tooth Disease, X-linked Recessive, 5
In affected males with X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), {13:Kim et al. (2007)} identified mutations in the PRPS1 gene ({311850.0009}; {311850.0010}). The phenotype includes peripheral neuropathy, sensorineural deafness, and visual impairment. {13:Kim et al. (2007)} used a positional cloning technique and evaluation of candidate genes known to be expressed in the cochlea to identify the PRPS1 gene for study. The mutations were shown to result in decreased enzyme activity; none of the affected individuals had increased uric acid or gout. {13:Kim et al. (2007)} noted that both PRPS1 superactivity and CMT5X phenotypes share neurologic features.
Arts Syndrome
Arts syndrome ({301835}) is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Using oligonucleotide microarray expression profiling of fibroblasts from 2 probands in a Dutch family with Arts syndrome, {11:de Brouwer et al. (2007)} found reduced expression levels of PRPS1. Sequencing of PRPS1 led to the identification of 2 different missense mutations: L152P ({311850.0011}) in the Dutch family and Q133P ({311850.0012}) in the Australian family. Both mutations resulted in a loss of PRPS1 activity, as was shown in silico by molecular modeling and was shown in vitro by enzyme assays in erythrocytes and fibroblasts from patients. This was in contrast to the gain-of-function mutations in PRPS1 identified in PRPS-related gout. The loss-of-function mutations of PRPS1 probably result in impaired purine biosynthesis, which was supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. {11:De Brouwer et al. (2007)} suggested that treatment with S-adenosylmethionine (SAM) theoretically could have therapeutic efficacy to replenish low levels of purine, and a clinical trial involving the 2 affected Australian brothers was underway. {10:De Brouwer et al. (2010)} reported preliminary results of the 2 Australian brothers with Arts syndrome.
X-linked Deafness 1
In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss (NSHL) mapping to the DNF2 locus (DFNX1; {304500}) on chromosome Xq22, {15:Liu et al. (2010)} analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; {311850.0013}) that cosegregated with the phenotype. Analysis of the PRPS1 gene in a British American DNF2 family, previously reported by {23:Tyson et al. (1996)}, revealed a different missense mutation (A87T; {311850.0014}); missense mutations were also detected in DFN2 families previously reported by {16:Manolis et al. (1999)} and {9:Cui et al. (2004)} ({311850.0015} and {311850.0016}, respectively). {15:Liu et al. (2010)} stated that none of the mutations were predicted to result in a major structural change in the PRPS1 protein, which might explain why the disease phenotype was limited to NSHL.|* {19:Roessler et al. (1990)} isolated a partial clone corresponding to the PRPS1 gene from a human lymphoblast cDNA library. The deduced PRPS1 protein has 318 amino acids and shares 95% amino acid homology with PRPS2. {3:Becker et al. (1990)} also cloned the PRPS1 gene and detected a 2.3-kb mRNA transcript.
By Northern blot analysis using rat Prps1 as probe, {22:Taira et al. (1989)} detected a 2.3-kb transcript in human adipose tissue, testis, and placenta and in 2 human cell lines.
{13:Kim et al. (2007)} demonstrated that the PRPS1 amino acid sequence shows an exceptionally high degree of conservation, with homologies greater than 95% across different species from zebrafish to human.|* {24:Wada et al. (1974)} and {12:Iinuma et al. (1975)} reported a Japanese infant with mental retardation, hypouricemia, megaloblastic changes in the bone marrow, and orotic aciduria associated with erythrocyte PRPS deficiency. Hypsarrhythmia was first observed at 10 months of age and markedly improved with ACTH therapy concomitant with an increase in red cell PRPS activity. However, studies in fibroblasts from this patient did not confirm enzyme deficiency ({2:Becker, 2001}).|* By the Goss-Harris method, {7:Becker et al. (1978)} concluded that the order of loci on chromosome Xq is G6PD ({305900})--HPRT1 ({308000})--PRPS1--alpha-GAL (GLA; {300644})--PGK1 ({311800})--centromere. {8:Becker et al. (1979)} assigned the PRPS1 locus to a position between the GLA and HPRT1 loci, particularly close to the latter, and discussed the functional significance of the proximity of the genes for their biochemically related functions.
{3:Becker et al. (1990)} mapped PRPS1 to Xq22-q24 by a combination of in situ hybridization and study of human/rodent somatic cell hybrids.
Pseudogene
By in situ chromosomal hybridization, {3:Becker et al. (1990)} identified a PRPS1-related gene or pseudogene (PRPS1L2) on chromosome 9q33-q34.|* Phosphoribosylpyrophosphate synthetase (PRPS; {EC 2.7.6.1}) catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis ({19:Roessler et al., 1990}). Three PRPS genes have been identified: the widely expressed PRPS1 and PRPS2 ({311860}) genes, which map to chromosome Xq22-q24 and Xp22, respectively, and PRPS3 (PRPS1L1; {611566}), which maps to chromosome 7 and appears to be transcribed only in testis ({2:Becker, 2001}).|* The PRPS1 gene spans over 30 kb and contains 7 exons ({2:Becker, 2001}). | PMID:10503584,PMID:15240907,PMID:168665,PMID:171280,PMID:17701896,PMID:17701900,PMID:1962753,PMID:20021999,PMID:20380929,PMID:2155397,PMID:217337,PMID:218284,PMID:22246954,PMID:2423135,PMID:24285972,PMID:2537655,PMID:4373874,PMID:6243137,PMID:7593598,PMID:8253776,PMID:8498830,PMID:8968763 |
|
OMIM | PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1 | | Deafness, X-linked 1 | X-linked | X | {10:De Brouwer et al. (2010)} provided a review of the clinical and molecular features of the 4 distinct syndromes caused by mutation in the PRPS1 gene: PRPS1 superactivity ({300661}), X-linked Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), Arts syndrome ({301835}), and isolated X-linked sensorineural deafness ({304500}). The neurologic phenotype in all 4 PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in 2 Australian brothers with Arts syndrome revealed some improvement of their condition, suggesting that SAM supplementation could potentially alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides.
Phosphoribosylpyrophosphate Synthetase Superactivity
In patients with phosphoribosylpyrophosphate synthetase superactivity ({300661}), {21,20:Roessler et al. (1991, 1993)} and {6:Becker et al. (1995)} identified mutations in the PRPS1 gene ({311850.0001}-{311850.0008}). All patients except 1 had hyperuricemia, neurodevelopmental abnormalities, and sensorineural deafness; the other patient had only hyperuricemia and gout. Functional expression studies of all mutations showed that enzyme overactivity was due to alteration of allosteric feedback mechanisms.
Charcot-Marie-Tooth Disease, X-linked Recessive, 5
In affected males with X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), {13:Kim et al. (2007)} identified mutations in the PRPS1 gene ({311850.0009}; {311850.0010}). The phenotype includes peripheral neuropathy, sensorineural deafness, and visual impairment. {13:Kim et al. (2007)} used a positional cloning technique and evaluation of candidate genes known to be expressed in the cochlea to identify the PRPS1 gene for study. The mutations were shown to result in decreased enzyme activity; none of the affected individuals had increased uric acid or gout. {13:Kim et al. (2007)} noted that both PRPS1 superactivity and CMT5X phenotypes share neurologic features.
Arts Syndrome
Arts syndrome ({301835}) is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Using oligonucleotide microarray expression profiling of fibroblasts from 2 probands in a Dutch family with Arts syndrome, {11:de Brouwer et al. (2007)} found reduced expression levels of PRPS1. Sequencing of PRPS1 led to the identification of 2 different missense mutations: L152P ({311850.0011}) in the Dutch family and Q133P ({311850.0012}) in the Australian family. Both mutations resulted in a loss of PRPS1 activity, as was shown in silico by molecular modeling and was shown in vitro by enzyme assays in erythrocytes and fibroblasts from patients. This was in contrast to the gain-of-function mutations in PRPS1 identified in PRPS-related gout. The loss-of-function mutations of PRPS1 probably result in impaired purine biosynthesis, which was supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. {11:De Brouwer et al. (2007)} suggested that treatment with S-adenosylmethionine (SAM) theoretically could have therapeutic efficacy to replenish low levels of purine, and a clinical trial involving the 2 affected Australian brothers was underway. {10:De Brouwer et al. (2010)} reported preliminary results of the 2 Australian brothers with Arts syndrome.
X-linked Deafness 1
In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss (NSHL) mapping to the DNF2 locus (DFNX1; {304500}) on chromosome Xq22, {15:Liu et al. (2010)} analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; {311850.0013}) that cosegregated with the phenotype. Analysis of the PRPS1 gene in a British American DNF2 family, previously reported by {23:Tyson et al. (1996)}, revealed a different missense mutation (A87T; {311850.0014}); missense mutations were also detected in DFN2 families previously reported by {16:Manolis et al. (1999)} and {9:Cui et al. (2004)} ({311850.0015} and {311850.0016}, respectively). {15:Liu et al. (2010)} stated that none of the mutations were predicted to result in a major structural change in the PRPS1 protein, which might explain why the disease phenotype was limited to NSHL.|* {19:Roessler et al. (1990)} isolated a partial clone corresponding to the PRPS1 gene from a human lymphoblast cDNA library. The deduced PRPS1 protein has 318 amino acids and shares 95% amino acid homology with PRPS2. {3:Becker et al. (1990)} also cloned the PRPS1 gene and detected a 2.3-kb mRNA transcript.
By Northern blot analysis using rat Prps1 as probe, {22:Taira et al. (1989)} detected a 2.3-kb transcript in human adipose tissue, testis, and placenta and in 2 human cell lines.
{13:Kim et al. (2007)} demonstrated that the PRPS1 amino acid sequence shows an exceptionally high degree of conservation, with homologies greater than 95% across different species from zebrafish to human.|* {24:Wada et al. (1974)} and {12:Iinuma et al. (1975)} reported a Japanese infant with mental retardation, hypouricemia, megaloblastic changes in the bone marrow, and orotic aciduria associated with erythrocyte PRPS deficiency. Hypsarrhythmia was first observed at 10 months of age and markedly improved with ACTH therapy concomitant with an increase in red cell PRPS activity. However, studies in fibroblasts from this patient did not confirm enzyme deficiency ({2:Becker, 2001}).|* By the Goss-Harris method, {7:Becker et al. (1978)} concluded that the order of loci on chromosome Xq is G6PD ({305900})--HPRT1 ({308000})--PRPS1--alpha-GAL (GLA; {300644})--PGK1 ({311800})--centromere. {8:Becker et al. (1979)} assigned the PRPS1 locus to a position between the GLA and HPRT1 loci, particularly close to the latter, and discussed the functional significance of the proximity of the genes for their biochemically related functions.
{3:Becker et al. (1990)} mapped PRPS1 to Xq22-q24 by a combination of in situ hybridization and study of human/rodent somatic cell hybrids.
Pseudogene
By in situ chromosomal hybridization, {3:Becker et al. (1990)} identified a PRPS1-related gene or pseudogene (PRPS1L2) on chromosome 9q33-q34.|* Phosphoribosylpyrophosphate synthetase (PRPS; {EC 2.7.6.1}) catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis ({19:Roessler et al., 1990}). Three PRPS genes have been identified: the widely expressed PRPS1 and PRPS2 ({311860}) genes, which map to chromosome Xq22-q24 and Xp22, respectively, and PRPS3 (PRPS1L1; {611566}), which maps to chromosome 7 and appears to be transcribed only in testis ({2:Becker, 2001}).|* The PRPS1 gene spans over 30 kb and contains 7 exons ({2:Becker, 2001}). | PMID:10503584,PMID:15240907,PMID:168665,PMID:171280,PMID:17701896,PMID:17701900,PMID:1962753,PMID:20021999,PMID:20380929,PMID:2155397,PMID:217337,PMID:218284,PMID:22246954,PMID:2423135,PMID:24285972,PMID:2537655,PMID:4373874,PMID:6243137,PMID:7593598,PMID:8253776,PMID:8498830,PMID:8968763 |
|
OMIM | PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1 | | Charcot-Marie-Tooth disease, X-linked recessive, 5 | X-linked recessive | X | {10:De Brouwer et al. (2010)} provided a review of the clinical and molecular features of the 4 distinct syndromes caused by mutation in the PRPS1 gene: PRPS1 superactivity ({300661}), X-linked Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), Arts syndrome ({301835}), and isolated X-linked sensorineural deafness ({304500}). The neurologic phenotype in all 4 PRPS1-related disorders seems to result primarily from reduced levels of GTP and possibly other purine nucleotides including ATP, suggesting that these disorders belong to the same disease spectrum. Preliminary results of S-adenosylmethionine (SAM) supplementation in 2 Australian brothers with Arts syndrome revealed some improvement of their condition, suggesting that SAM supplementation could potentially alleviate some of the symptoms of patients with PRPS1 spectrum diseases by replenishing purine nucleotides.
Phosphoribosylpyrophosphate Synthetase Superactivity
In patients with phosphoribosylpyrophosphate synthetase superactivity ({300661}), {21,20:Roessler et al. (1991, 1993)} and {6:Becker et al. (1995)} identified mutations in the PRPS1 gene ({311850.0001}-{311850.0008}). All patients except 1 had hyperuricemia, neurodevelopmental abnormalities, and sensorineural deafness; the other patient had only hyperuricemia and gout. Functional expression studies of all mutations showed that enzyme overactivity was due to alteration of allosteric feedback mechanisms.
Charcot-Marie-Tooth Disease, X-linked Recessive, 5
In affected males with X-linked recessive Charcot-Marie-Tooth disease-5 (CMTX5; {311070}), {13:Kim et al. (2007)} identified mutations in the PRPS1 gene ({311850.0009}; {311850.0010}). The phenotype includes peripheral neuropathy, sensorineural deafness, and visual impairment. {13:Kim et al. (2007)} used a positional cloning technique and evaluation of candidate genes known to be expressed in the cochlea to identify the PRPS1 gene for study. The mutations were shown to result in decreased enzyme activity; none of the affected individuals had increased uric acid or gout. {13:Kim et al. (2007)} noted that both PRPS1 superactivity and CMT5X phenotypes share neurologic features.
Arts Syndrome
Arts syndrome ({301835}) is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Using oligonucleotide microarray expression profiling of fibroblasts from 2 probands in a Dutch family with Arts syndrome, {11:de Brouwer et al. (2007)} found reduced expression levels of PRPS1. Sequencing of PRPS1 led to the identification of 2 different missense mutations: L152P ({311850.0011}) in the Dutch family and Q133P ({311850.0012}) in the Australian family. Both mutations resulted in a loss of PRPS1 activity, as was shown in silico by molecular modeling and was shown in vitro by enzyme assays in erythrocytes and fibroblasts from patients. This was in contrast to the gain-of-function mutations in PRPS1 identified in PRPS-related gout. The loss-of-function mutations of PRPS1 probably result in impaired purine biosynthesis, which was supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. {11:De Brouwer et al. (2007)} suggested that treatment with S-adenosylmethionine (SAM) theoretically could have therapeutic efficacy to replenish low levels of purine, and a clinical trial involving the 2 affected Australian brothers was underway. {10:De Brouwer et al. (2010)} reported preliminary results of the 2 Australian brothers with Arts syndrome.
X-linked Deafness 1
In a large 5-generation Chinese family segregating X-linked nonsyndromic hearing loss (NSHL) mapping to the DNF2 locus (DFNX1; {304500}) on chromosome Xq22, {15:Liu et al. (2010)} analyzed 14 candidate genes and identified a missense mutation in the PRPS1 gene (D65N; {311850.0013}) that cosegregated with the phenotype. Analysis of the PRPS1 gene in a British American DNF2 family, previously reported by {23:Tyson et al. (1996)}, revealed a different missense mutation (A87T; {311850.0014}); missense mutations were also detected in DFN2 families previously reported by {16:Manolis et al. (1999)} and {9:Cui et al. (2004)} ({311850.0015} and {311850.0016}, respectively). {15:Liu et al. (2010)} stated that none of the mutations were predicted to result in a major structural change in the PRPS1 protein, which might explain why the disease phenotype was limited to NSHL.|* {19:Roessler et al. (1990)} isolated a partial clone corresponding to the PRPS1 gene from a human lymphoblast cDNA library. The deduced PRPS1 protein has 318 amino acids and shares 95% amino acid homology with PRPS2. {3:Becker et al. (1990)} also cloned the PRPS1 gene and detected a 2.3-kb mRNA transcript.
By Northern blot analysis using rat Prps1 as probe, {22:Taira et al. (1989)} detected a 2.3-kb transcript in human adipose tissue, testis, and placenta and in 2 human cell lines.
{13:Kim et al. (2007)} demonstrated that the PRPS1 amino acid sequence shows an exceptionally high degree of conservation, with homologies greater than 95% across different species from zebrafish to human.|* {24:Wada et al. (1974)} and {12:Iinuma et al. (1975)} reported a Japanese infant with mental retardation, hypouricemia, megaloblastic changes in the bone marrow, and orotic aciduria associated with erythrocyte PRPS deficiency. Hypsarrhythmia was first observed at 10 months of age and markedly improved with ACTH therapy concomitant with an increase in red cell PRPS activity. However, studies in fibroblasts from this patient did not confirm enzyme deficiency ({2:Becker, 2001}).|* By the Goss-Harris method, {7:Becker et al. (1978)} concluded that the order of loci on chromosome Xq is G6PD ({305900})--HPRT1 ({308000})--PRPS1--alpha-GAL (GLA; {300644})--PGK1 ({311800})--centromere. {8:Becker et al. (1979)} assigned the PRPS1 locus to a position between the GLA and HPRT1 loci, particularly close to the latter, and discussed the functional significance of the proximity of the genes for their biochemically related functions.
{3:Becker et al. (1990)} mapped PRPS1 to Xq22-q24 by a combination of in situ hybridization and study of human/rodent somatic cell hybrids.
Pseudogene
By in situ chromosomal hybridization, {3:Becker et al. (1990)} identified a PRPS1-related gene or pseudogene (PRPS1L2) on chromosome 9q33-q34.|* Phosphoribosylpyrophosphate synthetase (PRPS; {EC 2.7.6.1}) catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the de novo and salvage pathways of purine and pyrimidine biosynthesis ({19:Roessler et al., 1990}). Three PRPS genes have been identified: the widely expressed PRPS1 and PRPS2 ({311860}) genes, which map to chromosome Xq22-q24 and Xp22, respectively, and PRPS3 (PRPS1L1; {611566}), which maps to chromosome 7 and appears to be transcribed only in testis ({2:Becker, 2001}).|* The PRPS1 gene spans over 30 kb and contains 7 exons ({2:Becker, 2001}). | PMID:10503584,PMID:15240907,PMID:168665,PMID:171280,PMID:17701896,PMID:17701900,PMID:1962753,PMID:20021999,PMID:20380929,PMID:2155397,PMID:217337,PMID:218284,PMID:22246954,PMID:2423135,PMID:24285972,PMID:2537655,PMID:4373874,PMID:6243137,PMID:7593598,PMID:8253776,PMID:8498830,PMID:8968763 |
|
OMIM | SARCOMA, SYNOVIAL, X BREAKPOINT 2; SSX2 | SARCOMA, SYNOVIAL, X-CHROMOSOME-RELATED 2, SSX2 | ?Sarcoma, synovial | | X | See SSX1 ({312820}) for a discussion of 2 genes located in Xp11.2, SSX1 and SSX2, one or the other of which is fused with the SYT gene (SS18; {600192}) in the translocation t(X;18) ({1:Crew et al., 1995}). | PMID:7539744 |
|
OMIM | TRACKING PROTEIN PARTICLE COMPLEX, SUBUNIT 2; TRAPPC2 | SEDLIN; SEDL, TRAPPC2, SEDL, SEDT | Spondyloepiphyseal dysplasia tarda | X-linked recessive | X | {12:Scrivens et al. (2011)} used tandem affinity purification-tagged TRAPPC2 and TRAPPC2L ({610970}) to identify purified TRAPP complexes from HEK293 cells. Knockdown of individual components of the TRAPP complexes caused Golgi fragmentation and arrested anterograde trafficking, suggesting that the TRAPP complex functions in an early trafficking step between the endoplasmic reticulum and Golgi. Gel filtration analysis suggested that TRAPP complexes can join to form larger oligomers.
{17:Venditti et al. (2012)} found that TANGO1 ({613455}) recruits sedlin, a TRAPP component that is defective in spondyloepiphyseal dysplasia tarda, and that sedlin is required for the ER export of procollagen, prefibrils of which are too large to fit into typical COPII vesicles. Sedlin bound and promoted efficient cycling of SAR1 ({603379}), a guanosine triphosphate that can constrict membranes, and thus allowed nascent carriers to grow and incorporate procollagen prefibrils. This joint action of TANGO1 and sedlin sustained the ER export of procollagen, and its derangement may explain the defective chondrogenesis underlying SEDT.|* {5:Gecz et al. (2000)} identified the genomic structure of the SEDL gene. The SEDL gene contains 6 exons and spans a genomic region of approximately 20 kb in Xp22. It has 4 Alu sequences in its 3-prime untranslated region (UTR) and an alternatively spliced MER20 sequence in its 5-prime UTR. Complex alternative splicing was detected for exon 4. {11:Mumm et al. (2001)} confirmed the structure of the SEDL gene and identified a potential splice variant lacking exon 2.|* {6:Gedeon et al. (1999)} determined that the SEDL gene maps to chromosome Xp22. {5:Gecz et al. (2000)} identified 7 SEDL pseudogenes in the human genome.|* {6:Gedeon et al. (1999)} identified 3 dinucleotide deletions in the SEDL gene in affected members of 3 Australian families with SEDT. All 3 mutations caused frameshifts that resulted in protein truncation, arousing speculation that less severe missense mutations of SEDL may have different phenotypic effects, such as precocious osteoarthritis only.
{7:Gedeon et al. (2001)} reviewed the spectrum of mutations found in 30 of 36 unrelated cases of X-linked SEDT ascertained from different ethnic populations. It brought the total number of different disease-associated mutations to 21 and showed that they were distributed throughout the SEDL gene. Four recurrent mutations accounted for 13 of the 30 (43%). Haplotype analyses and the diverse ethnic origins of the patients supported recurrent mutations. Two patients with large deletions of SEDL exons were found, 1 with childhood onset of painful complications, the other relatively free of additional symptoms. Since no clear genotype/phenotype correlation could be established, they concluded that the complete unaltered SEDL gene product is essential for normal bone growth.
{16:Tiller et al. (2001)} determined that the SEDL gene escapes X inactivation. They reported that the closest flanking genes identified at Xp22.2 also escape X inactivation. Clustering supported a model in which reasonable mechanisms may control the expression of genes that escape X inactivation. Most mutations in SEDL patients are predicted to truncate severely the protein product or eliminate it entirely. The observation that SEDL escapes X inactivation suggests that haploinsufficiency at the locus is inadequate to produce any phenotypic changes in female SEDL carriers. Although {18:Whyte et al. (1999)} observed subtle radiographic changes in older SEDL carriers, no signs or symptoms of premature osteoarthritis were noted in the women of the family reported by {16:Tiller et al. (2001)} or those reported by {6:Gedeon et al. (1999)}.
{2:Christie et al. (2001)} characterized the SEDL mutations in 4 unrelated spondyloepiphyseal dysplasia tarda kindreds of European origin. They identified 2 nonsense and 2 intragenic deletional frameshift mutations. The nonsense mutations occurred in exons 4 and 6. Both of the intragenic deletions, which were approximately 750 and 1300 to 1445 bp in size, involved intron 5 and part of exon 6 and resulted in frameshifts that led to premature termination signals.
{8:Grunebaum et al. (2001)} identified a missense mutation ({300202.0007}) in a 4-generation family with late-onset SED. {8:Grunebaum et al. (2001)} suggested that the mild phenotype in this family might be caused by a missense rather than a nonsense mutation.
The possibility that some mutations in the SEDL gene may result in a mild phenotype like that of early primary osteoarthritis prompted {4:Fiedler et al. (2002)} to collect a cohort of 37 male patients (age 50.6 +/- 7.6 years) with either early end-stage primary osteoarthritis of the hip (26 patients) or knee (11 patients). Cases with risk factors for secondary osteoarthritis, such as congenital hip dysplasia, rheumatoid arthritis, joint trauma, obesity, or diabetes mellitus, were excluded. Seven patients were stated to be the shortest in the family, while from 8 patients the father (with 158 cm), and from 4 the brother was the shortest member. Six fathers of the patients and 1 brother needed joint replacement because of end-stage osteoarthritis. {4:Fiedler et al. (2002)} detected no mutations in the coding sequence of SEDL and found no polymorphism indicating a highly conserved gene. Their findings supported previous results of high homology between different species ({7:Gedeon et al., 2001}; {5:Gecz et al., 2000}). The results indicated that mutations in the coding sequence of SEDL are not a common cause of early primary osteoarthritis in men.|* {9:Jang et al. (2002)} reported the 2.4-angstrom resolution structure of mouse SEDL, which revealed an unexpected similarity to the structures of the N-terminal regulatory domain of 2 SNAREs, Ykt6p ({606209}) and SEC22B ({604029}), despite no sequence homology to these proteins. The similarity and the presence of an unusually large number of solvent-exposed apolar residues of SEDL suggested that it serves regulatory and/or adaptor functions through multiple protein-protein interactions. {9:Jang et al. (2002)} noted that of the 4 known missense mutations responsible for SEDT, 3 map to the protein interior, where the mutations would disrupt the structure, and the fourth maps on a surface at which the mutation might abrogate functional interactions with a partner protein.|* The spondyloepiphyseal dysplasia tarda (SEDT; {313400}) locus had been mapped by linkage to Xp22 in the approximately 2-Mb interval between DXS16 and DXS987. {6:Gedeon et al. (1999)} confirmed and refined this localization to an interval of less than 170 kb by critical recombination events at DXS16 and AFMa124wc1 in 2 families. By genomic sequence analysis, they identified a novel gene, which they designated SEDL, within this region. The SEDL gene encodes a 140-amino acid protein, sedlin, with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport. Northern blot hybridization and RT-PCR analysis indicated that SEDL is widely expressed in tissues, including fibroblasts, lymphoblasts, and fetal cartilage. Two transcripts were detected by Northern blot analysis, one at approximately 2.8 kb encoding the X-linked SEDL and the other at approximately 0.75 kb encoding the truncated transcript of the chromosome 19 pseudogene. The latter is a processed pseudogene with an additional exon 5-prime to the rest of the pseudogene and separated by its sole intron. {6:Gedeon et al. (1999)} identified SEDL homologs in yeast, Drosophila, Caenorhabditis elegans, mouse, and rat. The yeast homolog was characterized as a member of a large multiprotein complex called TRAPP (transport protein particle), which has a role in the targeting and fusion of the ER-to-Golgi transport vesicles with their acceptor compartment.
By Northern blot analysis, {11:Mumm et al. (2001)} detected additional minor SEDL transcripts of 5.0 and 1.6 kb, the smallest of which may reflect a pseudogene.
{5:Gecz et al. (2000)} performed transient transfection studies with tagged recombinant mammalian SEDL proteins in COS-7 cells. The tagged SEDL proteins localized to the perinuclear structures that partly overlapped with the intermediate ER-Golgi compartment. Two human SEDL mutations introduced into SEDL FLAG and GFP constructs led to the misplacement of the SEDL protein primarily to the cell nucleus and partially to the cytoplasm.|* TRAPPC2 is a component of the TRAPP multisubunit tethering complex involved in intracellular vesicle trafficking ({12:Scrivens et al., 2011}). | PMID:10431248,PMID:10999831,PMID:11031107,PMID:11326333,PMID:11349230,PMID:11424925,PMID:11443194,PMID:11595175,PMID:12030902,PMID:12123495,PMID:12361953,PMID:12446987,PMID:12919139,PMID:14755465,PMID:21525244,PMID:23019651,PMID:23656395,PMID:9990351 |
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OMIM | STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC1A | SMC1-ALPHA;;
STRUCTURAL MAINTENANCE OF CHROMOSOMES 1-LIKE 1; SMC1L1;;
SMC1;;
DXS423E;;
KIAA0178, DXS423E, SMC1, CDLS2 | Cornelia de Lange syndrome 2 | | X | {12:Rocques et al. (1995)} showed that the DXS423E gene maps to a cosmid contig that lies centromeric to the OATL2 locus (see {258870}) at Xp11.2. {1:Brown et al. (1995)} showed that SMC1 escapes X-chromosome inactivation. SMC1 and XE169 ({314690}) were thought to define a new region in the proximal short arm of the X chromosome that escapes X inactivation. The corresponding gene in the mouse, Sb1.8, is located at the distal end of the X chromosome and is subject to X inactivation ({13:Sultana et al., 1995}).|* A female with a Cornelia de Lange syndrome ({122470}) phenotype carrying an apparently balanced X;8 translocation involving the Xp11.2 band, to which the SMC1L1 gene maps, was described by {3:Egemen et al. (2005)}. The findings are consistent with the location of the SMC1L1 gene at Xp11.2 and the involvement of that gene in X-linked Cornelia de Lange syndrome ({300590}).
{10:Musio et al. (2006)} recruited 53 unrelated and 4 related individuals with a diagnosis of Cornelia de Lange syndrome, encompassing the entire spectrum of phenotypes. They found pathogenic NIPBL ({608667}) mutations in 24 of them, whereas the remaining 33 cases did not bear any NIPBL mutation. Of these 33 individuals, there was only 1 instance of familial occurrence, with 2 male sibs, their mother, and a first cousin affected. Involvement of the NIPBL gene was excluded in this family, but the affected individuals were found to carry a 3-bp deletion in the SMC1L1 gene ({300040.0001}). In addition, a sporadic case was found to have a de novo missense mutation in the SMC1L1 gene ({300040.0002}).
{2:Deardorff et al. (2007)} identified 14 additional SMC1A mutations in patients with a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Analysis of the mutant SMC1A proteins indicated that they were likely to produce functional cohesin complexes; however, {2:Deardorff et al. (2007)} posited that they mutations may alter their chromosome binding dynamics. Ten of 14 SMC1A-mutation-positive individuals with CDLS identified by {2:Deardorff et al. (2007)} were female. Furthermore, their series included similarly affected male and female probands, implying an X-linked dominant mode of expression. Several males were rather mildly affected and no more severely affected than many of the SMC1A mutation-positive females. Since the SMC1A gene escapes X inactivation ({1:Brown et al., 1995}), it is likely that the mechanism in affected females is due to a dominant-negative effect of the altered protein and less likely that it is due to decreased protein levels or skewed X inactivation. Consistent with this dominant-negative effect on cohesin, {2:Deardorff et al. (2007)} described a single amino acid deletion mutation in the SMC3 gene underlying a variant Cornelia de Lange syndrome ({606062.0001}). The data indicated that SMC3 and SMC1A mutations contribute to approximately 5% of cases of Cornelia de Lange syndrome, result in a consistently mild phenotype with absence of major structural anomalies typically associated with CDLS, such as those of the limbs, and, in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation. {2:Deardorff et al. (2007)} suggested that it may be found that additional 'cohesinopathies' result from perturbation of the more than 15 additional components of this complex that had yet to be associated with human disorders.|* Genetic marker SB1.8 (DXS423E) was originally identified as a cross-reacting clone during the screening of a human lymphocyte cDNA library with an oligonucleotide probe corresponding to the CYBB ({300481}) gene, which maps to Xp21.1. {12:Rocques et al. (1995)} found that the DXS423E gene encodes a protein of 1,233 amino acids that is 30% identical to the essential yeast protein SMC1 (structural maintenance of chromosomes-1), which is required for the segregation of chromosomes at mitosis. Both the human protein, called SB1.8, and SMC1 contain an N-terminal NTP-binding site, a central coiled-coil region, and a C-terminal helix-loop-helix domain, and both have structural features in common with the force-generating proteins myosin and kinesin. SB1.8 also exhibits regions of homology and overall structural similarity to protein 115p of the prokaryote Mycoplasma hyorhinis.|* See SCC1 ({606462}) and {14:Sumara et al. (2000)} for information on the role of SMC1 in cohesin association with and dissociation from chromosomes.
In yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 and Smc3 ({606062}) subunits are rod-shaped molecules with globular ABC-like ATPases at one end and dimerization domains at the other, connected by long coiled coils. Smc1 and Smc3 associate to form V-shaped heterodimers. Their ATPase heads are thought to be bridged by a third subunit, Scc1, creating a huge triangular ring that can trap sister DNA molecules. {4:Gruber et al. (2003)} studied whether cohesin forms such rings in vivo. Proteolytic cleavage of Scc1 by separase at the onset of anaphase triggers its dissociation from chromosomes. The authors showed that N- and C-terminal Scc1 cleavage fragments remain connected due to their association with different heads of a single Smc1/Smc3 heterodimer. Cleavage of the Smc3 coiled coil was sufficient to trigger cohesin release from chromosomes and loss of sister cohesion, consistent with a topologic association with chromatin.
{9:Musio et al. (2005)} demonstrated that RNA interference (RNAi) of SMC1 was sufficient to induce fragile site expression in normal human fibroblasts. They showed that aphidicolin treatment led to an increase in SMC1 synthesis, SMC1 phosphorylation via an ATR ({601215})-dependent pathway, and enhanced double-stranded break induction as visualized by immunohistochemical studies with phosphorylated H2AX ({601772}). Discrete nuclear foci were absent or very rare after 1 or 2 hours exposure to aphidicolin and/or RNAi of SMC1 but became more numerous and distinct after 6 hours. {9:Musio et al. (2005)} proposed that fragile sites might be viewed as an in vitro phenomenon originating from double-strand breaks formed because of stalled DNA replication that lasted too long to be rescued via the ATR/SMC1 axis, whereas in vivo, following an extreme replication block, rare cells could escape checkpoint mechanisms and enter mitosis with a defect in genome assembly, eventually leading to neoplastic transformation.
Cohesin's Scc1 ({606462}), Smc1, and Smc3 ({606062}) subunits form a tripartite ring structure, and it had been proposed that cohesin holds sister DNA molecules together by trapping them inside its ring. To test this, {5:Haering et al. (2008)} used site-specific crosslinking to create chemical connections at the 3 interfaces between the 3 constituent polypeptides of the ring, thereby creating covalently closed cohesin rings. As predicted by the ring entrapment model, this procedure produced dimeric DNA-cohesin structures that are resistant to protein denaturation. {5:Haering et al. (2008)} concluded that cohesin rings concatenate individual sister minichromosome DNA molecules.
{7:Kagey et al. (2010)} reported that Mediator (see MED8, {607956}) and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect 2 DNA segments. The cohesin-loading factor NIPBL ({608667}) is associated with Mediator-cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by Mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell type-specific DNA loops linked to the gene expression program of each cell. | PMID:11076961,PMID:12654244,PMID:15640246,PMID:15844775,PMID:16604071,PMID:17273969,PMID:18596691,PMID:18996922,PMID:20635401,PMID:20720539,PMID:22106055,PMID:7757074,PMID:7757075,PMID:7757076 |
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