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VPS35 mutations in Parkinson disease.

The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.

Pubmed ID: 21763482 RIS Download

Mesh terms: Adult | Age of Onset | Amino Acid Sequence | Biological Transport | Endosomes | Female | Gene Expression Regulation | Genetic Variation | Genome, Human | Humans | Male | Middle Aged | Molecular Sequence Data | Mutation | Parkinson Disease | Pedigree | Vacuoles | Vesicular Transport Proteins | trans-Golgi Network

Research resources used in this publication

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Data used in this publication

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Associated grants

  • Agency: NINDS NIH HHS, Id: P50 NS040256
  • Agency: Medical Research Council, Id: G0600705
  • Agency: Medical Research Council, Id: G0800582
  • Agency: NINDS NIH HHS, Id: P50NS072187
  • Agency: NINDS NIH HHS, Id: P50NS040256
  • Agency: NINDS NIH HHS, Id: P50 NS072187

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dbGaP at NCBI

Database to archive and distribute the results of studies that have investigated the interaction of genotype and phenotype, including genome-wide association studies, medical sequencing, molecular diagnostic assays, and association between genotype and non-clinical traits. dbGaP provides two types of access for users, open and controlled. Summaries of studies and the contents of measured variables as well as original study document text are generally available to the public, while access to individual-level data including phenotypic data tables and genotypes require varying levels of authorization. The data in dbGaP will be pre-competitive, and will not be protected by intellectual property patents. Investigators who agree to the terms of dbGaP data use may not restrict other investigators' use of primary dbGaP data by filing intellectual property patents on it. However, the use of primary data from dbGaP to develop commercial products and tests to meet public health needs is encouraged. Submitters who are not Federally-funded and affiliated with an NIH IC will need to work with an NIH DAC so that proposed submission can be reviewed for consistency with appropriate policies to protect the privacy of research participants and confidentiality of their data. Submissions to dbGaP will not be accepted without assurance that the submitting institution approves the submission and has verified that the data submission is consistent with all applicable laws and regulations, as well as institutional policies. Submitters must also identify any limits on research uses of the data that are specifically set by individual research participants, e.g., through their informed consent. Open-access data can be browsed online or downloaded from dbGaP without prior permission or authorization.

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OMIM

Collection of human genes and genetic phenotypes, focusing on the relationship between phenotype and genotype. The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and a variety of related genes. It is updated daily, and the entries contain copious links to other genetics resources.

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PDGene - A database for Parkinsons disease genetic association studies

The PDGene database aims to provide a comprehensive, unbiased and regularly updated collection of genetic association studies performed on Parkinson's disease (PD) phenotypes. Eligible publications are identified following systematic searches of scientific literature databases, as well as the table of contents of journals in genetics, neurology, and psychiatry. The database can be searched either by a variety of dropdown menus or by specific keywords. For each gene, summary overviews are provided displaying key characteristics for each publication, including links to genotype distributions of the polymorphisms studied, random-effects allelic meta-analyses, and funnel plots for an assessment of publication bias. The PDGene database, developed by Massachusetts General Hospital/Harvard Medical School, The Michael J. Fox Foundation and the Alzheimer Research Forum, is supported by a grant from The Michael J. Fox Foundation in partnership with the Alzheimer Research Forum.

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