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. 2011 Jul 15;89(1):168-75.
doi: 10.1016/j.ajhg.2011.06.008.

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease

Alexander Zimprich  1 , Anna Benet-Pagès, Walter Struhal, Elisabeth Graf, Sebastian H Eck, Marc N Offman, Dietrich Haubenberger, Sabine Spielberger, Eva C Schulte, Peter Lichtner, Shaila C Rossle, Norman Klopp, Elisabeth Wolf, Klaus Seppi, Walter Pirker, Stefan Presslauer, Brit Mollenhauer, Regina Katzenschlager, Thomas Foki, Christoph Hotzy, Eva Reinthaler, Ashot Harutyunyan, Robert Kralovics, Annette Peters, Fritz Zimprich, Thomas Brücke, Werner Poewe, Eduard Auff, Claudia Trenkwalder, Burkhard Rost, Gerhard Ransmayr, Juliane Winkelmann, Thomas Meitinger, Tim M Strom
Affiliations

A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease

Alexander Zimprich et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
Pedigrees of Families A, B, and C Unaffected family members are indicated by open symbols, affected members by closed symbols. Asterisks denote individuals genotyped for p.Asp620Asn. To maintain confidentiality, we have not shown genotypes of unaffected individuals. A question mark within a symbol denotes an unknown phenotype. Diagonal bars through symbols denote deceased individuals.
Figure 2
Figure 2
Hydrogen-Bonding Capacities for Wild-Type Asp620 and Arg524 and the Variants p.Asp620Asn and p.Arg524Trp Hydrogen bonds (HB) are shown as red dashed lines. Asp60 and Arg524 are in green; p.Asp620Asn and p.Arg524Trp are in orange. (A) Asp620 forms a HB to Lys622 and shows an additional salt-bridge interaction. p.Asp620Asn forms fewer HBs, and no electrostatic interaction is possible. (B) Arg524 forms a HB network with Asp483 and Asp486. This network is broken by the p.Arg524Trp substitution.
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