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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
VPS35 mutations in parkinson disease
American Journal of Human Genetics, Volume 89, No. 1, Year 2011
Notification
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Description
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 doparesponsive 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. © 2011 by The American Society of Human Genetics. All rights reserved.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3135796/bin/mmc1.pdf
Authors & Co-Authors
Vilarino-Guell, Carles
Canada, Vancouver
The University of British Columbia
Wider, Christian
Switzerland, Lausanne
Centre Hospitalier Universitaire Vaudois
Ross, Owen A.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Dächsel, Justus C.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Kachergus, Jennifer M.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Lincoln, Sarah J.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Soto-Ortolaza, Alexandra I.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Cobb, Stephanie A.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Wilhoite, Greggory J.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Bacon, Justin A.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Bahareh Behrouz,
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Melrose, Heather L.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Hentati, Emna
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Puschmann, Andreas J.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Sweden, Lund
Lunds Universitet
Evans, Daniel M.
Canada, Vancouver
The University of British Columbia
Conibear, Elizabeth
Canada, Vancouver
The University of British Columbia
Wasserman, Wyeth W.
Canada, Vancouver
The University of British Columbia
Aasly, Jan Olav
Norway, Trondheim
Universitetssykehuset I Trondheim
Burkhard, Pierre R.
Switzerland, Geneva
Hôpitaux Universitaires de Genève
Djaldetti, Ruth
Israel, Tel Aviv-yafo
Tel Aviv University
Ghika, Joseph
Switzerland, Lausanne
Centre Hospitalier Universitaire Vaudois
Hentati, F. F.
Tunisia, Tunis
Institut National de Neurologie Mongi-ben Hamida
Krygowska-Wajs, Anna
Poland, Krakow
Jagiellonian University Medical College
Lynch, Timothy L.
Ireland, Dublin
Mater Misericordiae University Hospital
Ireland, Dublin
University College Dublin
Melamed, Eldad
Israel, Tel Aviv-yafo
Tel Aviv University
Rajput, Alex H.
Canada, Saskatoon
University of Saskatchewan, College of Medicine
Rajput, Ali H.
Canada, Saskatoon
University of Saskatchewan, College of Medicine
Solida, Alessandra
Switzerland, Lausanne
Centre Hospitalier Universitaire Vaudois
Wu, Ruey Meei
Taiwan, Taipei
National Taiwan University Hospital
Uitti, Ryan J.
United States, Jacksonville
Mayo Clinic in Jacksonville, Florida
Wszołek, Zbigniew K.
Switzerland, Lausanne
Centre Hospitalier Universitaire Vaudois
Vingerhoets, François
Switzerland, Lausanne
Centre Hospitalier Universitaire Vaudois
Farrer, Matthew J.
Canada, Vancouver
The University of British Columbia
Switzerland, Lausanne
Centre Hospitalier Universitaire Vaudois
Statistics
Citations: 828
Authors: 33
Affiliations: 13
Identifiers
Doi:
10.1016/j.ajhg.2011.06.001
ISSN:
00029297
e-ISSN:
15376605
Research Areas
Cancer
Genetics And Genomics
Health System And Policy