Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. We use triple-SILAC mass spectrometry to quantify proteomes from human pedigrees affected by mutations in ATP7A, which cause Menkes disease, a rare neurodegenerative and neurodevelopmental disorder stemming from systemic copper depletion. We identified 214 proteins whose expression was altered in ATP7A-/y fibroblasts. Bioinformatic analysis of ATP7A-mutant proteomes identified known phenotypes and processes affected in rare genetic diseases causing copper dyshomeostasis, including altered mitochondrial function. We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes.
Pubmed ID: 29397366 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Collects, maintains and distributes Drosophila melanogaster strains for research. Emphasis is placed on genetic tools that are useful to a broad range of investigations. These include basic stocks of flies used in genetic analysis such as marker, balancer, mapping, and transposon-tagging strains; mutant alleles of identified genes, including a large set of transposable element insertion alleles; defined sets of deficiencies and a variety of other chromosomal aberrations; engineered lines for somatic and germline clonal analysis; GAL4 and UAS lines for targeted gene expression; enhancer trap and lacZ-reporter strains with defined expression patterns for marking tissues; and a collection of transposon-induced lethal mutations.
View all literature mentionsThis monoclonal targets MTCO1
View all literature mentionsThis polyclonal targets GSTM3
View all literature mentionsThis polyclonal secondary targets IgG1
View all literature mentionsThis monoclonal targets ATP7A (D-9)
View all literature mentionsThis monoclonal targets CD9 antibody [EPR2949]
View all literature mentionsThis polyclonal secondary targets IgG, IgM, IgA (H+L)
View all literature mentionsThis polyclonal targets Human Glutaredoxin 1
View all literature mentionsThis monoclonal targets SDHA
View all literature mentionsThis monoclonal targets Clathrin Heavy Chain
View all literature mentionsThis unknown targets HORSERADISH PEROXIDASE
View all literature mentionsThis monoclonal targets Human QPRT
View all literature mentionsThis monoclonal targets Hsp90
View all literature mentionsThis polyclonal targets GSTT1
View all literature mentionsThis monoclonal targets Clathrin Heavy Chain
View all literature mentionsThis polyclonal targets Tom20 (FL-145)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets slightly modified β-cytoplasmic actin N-terminal peptide, Ac-Asp-Asp-Asp-Ile-Ala-Ala-Leu-Val-Ile-Asp-Asn-Gly-Ser-Gly-Lys, conjugated to KLH
View all literature mentionsThis monoclonal targets mEPHX
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets SLC25A1
View all literature mentionsThis monoclonal targets Copper ATPase 1 (Menke's disease protein)
View all literature mentionsDrosophila melanogaster with name w[1118]; P{GD11265}v26468 from Flybase.
View all literature mentionsCell line GM00245 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name B6;129P2-Uchl1tm1Dgen/Mmnc from MMRRC.
View all literature mentionsDrosophila melanogaster with name w[1118]; P{w[+mC]=Ddc-GAL4.L}Lmpt[4.36] from BDSC.
View all literature mentionsDrosophila melanogaster with name P{w[+mW.hs]=GawB}elav[C155] from BDSC.
View all literature mentionsCell line GM01057 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name C57BL/6-Atp7aMo-br/J from IMSR.
View all literature mentionsDrosophila melanogaster with name y[1] w[1118]; P{w[+mW.hs]=GawB}pnr[MD237]/TM3, P{w[+mC]=UAS-y.C}MC2, Ser[1] from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118] from BDSC.
View all literature mentionsDrosophila melanogaster with name P{KK100396}VIE-260B from Flybase.
View all literature mentionsCell line GM01983 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsData analysis, graphing, and management application that allows users to import, manipulate, analyze data, and create customized plots. Plots include x-y probability, histogram, box, percentile, horizontal bar, stack bar, column, stack column, polar, and pie. Binned data can be exported to a histogram, step plot, or spike plot. KaleidaGraph works with Windows and Macintosh systems.
View all literature mentionsSoftware for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
View all literature mentionsLight cycler software for analysis of quatitative real time PCR
View all literature mentionsUser interface software for Carl Zeiss light microscopy imaging systems. ZEN is the universal user interface you will see on every imaging system from ZEISS. After selecting fluorophore, ZEN applies the necessary settings to collect and organize data.
View all literature mentionsSoftware package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.
View all literature mentionsCell line GM00220 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line GM04068 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line GM01981 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets slightly modified β-cytoplasmic actin N-terminal peptide, Ac-Asp-Asp-Asp-Ile-Ala-Ala-Leu-Val-Ile-Asp-Asn-Gly-Ser-Gly-Lys, conjugated to KLH
View all literature mentionsThis monoclonal targets MTCO1
View all literature mentionsThis polyclonal targets Tom20 (FL-145)
View all literature mentionsThis monoclonal targets SDHA
View all literature mentionsThis monoclonal targets Human QPRT
View all literature mentionsThis monoclonal targets ATP7A (D-9)
View all literature mentionsThis polyclonal targets Human Glutaredoxin 1
View all literature mentionsThis monoclonal targets mEPHX
View all literature mentionsThis polyclonal targets GSTM3
View all literature mentionsThis monoclonal targets CD9 antibody [EPR2949]
View all literature mentionsThis polyclonal targets GSTT1
View all literature mentionsCell line GM01057 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis unknown targets HORSERADISH PEROXIDASE
View all literature mentionsThis polyclonal secondary targets IgG, IgM, IgA (H+L)
View all literature mentionsThis polyclonal secondary targets IgG1
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsCell line GM01983 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets Clathrin Heavy Chain
View all literature mentionsThis monoclonal targets Hsp90
View all literature mentionsThis monoclonal targets Clathrin Heavy Chain
View all literature mentionsDrosophila melanogaster with name w[1118]; P{w[+mC]=Ddc-GAL4.L}Lmpt[4.36] from BDSC.
View all literature mentionsMus musculus with name B6;129P2-Uchl1tm1Dgen/Mmnc from MMRRC.
View all literature mentionsDrosophila melanogaster with name P{w[+mW.hs]=GawB}elav[C155] from BDSC.
View all literature mentionsMus musculus with name C57BL/6-Atp7aMo-br/J from IMSR.
View all literature mentionsDrosophila melanogaster with name w[1118] from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] w[1118]; P{w[+mW.hs]=GawB}pnr[MD237]/TM3, P{w[+mC]=UAS-y.C}MC2, Ser[1] from BDSC.
View all literature mentionsCell line GM00245 is a Finite cell line with a species of origin Homo sapiens (Human)
View all literature mentionsDrosophila melanogaster with name P{KK100396}VIE-260B from Flybase.
View all literature mentionsDrosophila melanogaster with name w[1118]; P{GD11265}v26468 from Flybase.
View all literature mentionsMus musculus with name B6;129P2-Uchl1tm1Dgen/Mmnc from MMRRC.
View all literature mentions