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Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.

P450 oxidoreductase (POR) is the obligatory flavoprotein intermediate that transfers electrons from reduced nicotinamide adenine dinucleotide phosphate (NADPH) to all microsomal cytochrome P450 enzymes. Although mouse Por gene ablation causes embryonic lethality, POR missense mutations cause disordered steroidogenesis, ambiguous genitalia, and Antley-Bixler syndrome (ABS), which has also been attributed to fibroblast growth factor receptor 2 (FGFR2) mutations. We sequenced the POR gene and FGFR2 exons 8 and 10 in 32 individuals with ABS and/or hormonal findings that suggested POR deficiency. POR and FGFR2 mutations segregated completely. Fifteen patients carried POR mutations on both alleles, 4 carried mutations on only one allele, 10 carried FGFR2 or FGFR3 mutations, and 3 patients carried no mutations. The 34 affected POR alleles included 10 with A287P (all from whites) and 7 with R457H (four Japanese, one African, two whites); 17 of the 34 alleles carried 16 "private" mutations, including 9 missense and 7 frameshift mutations. These 11 missense mutations, plus 10 others found in databases or reported elsewhere, were recreated by site-directed mutagenesis and were assessed by four assays: reduction of cytochrome c, oxidation of NADPH, support of 17alpha-hydroxylase activity, and support of 17,20 lyase using human P450c17. Assays that were based on cytochrome c, which is not a physiologic substrate for POR, correlated poorly with clinical phenotype, but assays that were based on POR's support of catalysis by P450c17--the enzyme most closely associated with the hormonal phenotype--provided an excellent genotype/phenotype correlation. Our large survey of patients with ABS shows that individuals with an ABS-like phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct new disease: POR deficiency.

Pubmed ID: 15793702 RIS Download

Mesh terms: Abnormalities, Multiple | Amino Acid Sequence | Craniosynostoses | Female | Genetic Variation | Genitalia | Humans | Infant | Infant, Newborn | Male | Models, Molecular | Molecular Sequence Data | Mutation | NADPH-Ferrihemoprotein Reductase | Receptor Protein-Tyrosine Kinases | Receptor, Fibroblast Growth Factor, Type 2 | Receptors, Fibroblast Growth Factor | Sequence Alignment | Steroids | Syndrome

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Associated grants

  • Agency: NIGMS NIH HHS, Id: R01 GM073020
  • Agency: NICHD NIH HHS, Id: R01 HD041958
  • Agency: NIDDK NIH HHS, Id: R01 DK37922
  • Agency: NIDDK NIH HHS, Id: K01 DK002939
  • Agency: NIDCR NIH HHS, Id: P60 DE013078
  • Agency: NIDDK NIH HHS, Id: KO1 DK02939
  • Agency: NCRR NIH HHS, Id: M01 RR000052
  • Agency: NICHD NIH HHS, Id: R01 HD41958
  • Agency: NIGMS NIH HHS, Id: R01 GM73020
  • Agency: NIDDK NIH HHS, Id: R01 DK037922
  • Agency: NCRR NIH HHS, Id: M01 RR00052

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Software for DNA sequencing analysis that integates with Sanger Sequencing files generated by Applied Biosystems Genetic Analyzers, MegaBACE, and Beckman CEQ electrophoresis systems. It can be used to find single nucleotide polymorphisms (SNPs), insertions and deletions (INDELS), and somatic mutations in direct sequencing, PCR sequencing, mitochondrial DNA sequencing, and resequencing projects.

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Command line version of multiple sequence alignment program Clustal for DNA or proteins. Alignment is progressive and considers sequence redundancy. No longer being maintained. Please consider using Clustal Omega instead which accepts nucleic acid or protein sequences in multiple sequence formats NBRF/PIR, EMBL/UniProt, Pearson (FASTA), GDE, ALN/ClustalW, GCG/MSF, RSF.

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