title: A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease.
abstract: To identify rare causal variants in late-onset Parkinson disease (PD), we investigated an Austrian family with 16 affected individuals by exome sequencing. We found a missense mutation, c.1858G>A (p.Asp620Asn), in the VPS35 gene in all seven affected family members who are alive. By screening additional PD cases, we saw the same variant cosegregating with the disease in an autosomal-dominant mode with high but incomplete penetrance in two further families with five and ten affected members, respectively. The mean age of onset in the affected individuals was 53 years. Genotyping showed that the shared haplotype extends across 65 kilobases around VPS35. Screening the entire VPS35 coding sequence in an additional 860 cases and 1014 controls revealed six further nonsynonymous missense variants. Three were only present in cases, two were only present in controls, and one was present in cases and controls. The familial mutation p.Asp620Asn and a further variant, c.1570C>T (p.Arg524Trp), detected in a sporadic PD case were predicted to be damaging by sequence-based and molecular-dynamics analyses. VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer disease.
authors.affiliation: Department of Neurology, Medizinische Universität Wien, Vienna, Austria. alexander.zimprich@meduniwien.ac.at
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimprich
authors.forename: Anna
authors.initials: A
authors.lastname: Benet-Pagès
authors.forename: Walter
authors.initials: W
authors.lastname: Struhal
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.forename: Sebastian H
authors.initials: SH
authors.lastname: Eck
authors.forename: Marc N
authors.initials: MN
authors.lastname: Offman
authors.forename: Dietrich
authors.initials: D
authors.lastname: Haubenberger
authors.forename: Sabine
authors.initials: S
authors.lastname: Spielberger
authors.forename: Eva C
authors.initials: EC
authors.lastname: Schulte
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Shaila C
authors.initials: SC
authors.lastname: Rossle
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Wolf
authors.forename: Klaus
authors.initials: K
authors.lastname: Seppi
authors.forename: Walter
authors.initials: W
authors.lastname: Pirker
authors.forename: Stefan
authors.initials: S
authors.lastname: Presslauer
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.forename: Regina
authors.initials: R
authors.lastname: Katzenschlager
authors.forename: Thomas
authors.initials: T
authors.lastname: Foki
authors.forename: Christoph
authors.initials: C
authors.lastname: Hotzy
authors.forename: Eva
authors.initials: E
authors.lastname: Reinthaler
authors.forename: Ashot
authors.initials: A
authors.lastname: Harutyunyan
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: Fritz
authors.initials: F
authors.lastname: Zimprich
authors.forename: Thomas
authors.initials: T
authors.lastname: Brücke
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Eduard
authors.initials: E
authors.lastname: Auff
authors.forename: Claudia
authors.initials: C
authors.lastname: Trenkwalder
authors.forename: Burkhard
authors.initials: B
authors.lastname: Rost
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ransmayr
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D006860:Hydrogen Bonding; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D011487:Protein Conformation; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins