title: VPS35 mutations in Parkinson disease.
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 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.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada. carles@can.ubc.ca
authors.forename: Carles
authors.initials: C
authors.lastname: Vilariño-Güell
authors.forename: Christian
authors.initials: C
authors.lastname: Wider
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Justus C
authors.initials: JC
authors.lastname: Dachsel
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kachergus
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lincoln
authors.forename: Alexandra I
authors.initials: AI
authors.lastname: Soto-Ortolaza
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Cobb
authors.forename: Greggory J
authors.initials: GJ
authors.lastname: Wilhoite
authors.forename: Justin A
authors.initials: JA
authors.lastname: Bacon
authors.forename: Bahareh
authors.initials: B
authors.lastname: Behrouz
authors.forename: Heather L
authors.initials: HL
authors.lastname: Melrose
authors.forename: Emna
authors.initials: E
authors.lastname: Hentati
authors.forename: Andreas
authors.initials: A
authors.lastname: Puschmann
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Evans
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Conibear
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Burkhard
authors.forename: Ruth
authors.initials: R
authors.lastname: Djaldetti
authors.forename: Joseph
authors.initials: J
authors.lastname: Ghika
authors.forename: Faycal
authors.initials: F
authors.lastname: Hentati
authors.forename: Anna
authors.initials: A
authors.lastname: Krygowska-Wajs
authors.forename: Tim
authors.initials: T
authors.lastname: Lynch
authors.forename: Eldad
authors.initials: E
authors.lastname: Melamed
authors.forename: Alex
authors.initials: A
authors.lastname: Rajput
authors.forename: Ali H
authors.initials: AH
authors.lastname: Rajput
authors.forename: Alessandra
authors.initials: A
authors.lastname: Solida
authors.forename: Ruey-Meei
authors.initials: RM
authors.lastname: Wu
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Uitti
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: François
authors.initials: F
authors.lastname: Vingerhoets
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D001692:Biological Transport; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D014617:Vacuoles / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins