VPS35 mutations in parkinson disease
Journal
American Journal of Human Genetics
Journal Volume
89
Journal Issue
1
Pages
162-167
Date Issued
2011
Author(s)
Vilari?o-G?ell C
Wider C
Ross O.A
Dachsel J.C
Kachergus J.M
Lincoln S.J
Soto-Ortolaza A.I
Cobb S.A
Wilhoite G.J
Bacon J.A
Bahareh Behrouz, Melrose H.L
Hentati E
Puschmann A
Evans D.M
Conibear E
Wasserman W.W
Aasly J.O
Burkhard P.R
Djaldetti R
Ghika J
Hentati F
Krygowska-Wajs A
Lynch T
Melamed E
Rajput A
Rajput A.H
Solida A
Uitti R.J
Wszolek Z.K
Vingerhoets F
Farrer M.J.
Abstract
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.
SDGs
Other Subjects
asparagine; aspartic acid; cell protein; unclassified drug; vacuolar protein sorting 35; adult; article; biogenesis; controlled study; exome; gene mutation; gene sequence; genetic analysis; genetic variability; human; lysosome; major clinical study; Parkinson disease; parkinsonism; pathogenicity; pedigree; priority journal; trans Golgi network; tremor
Type
journal article