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.

Figure 1

Pedigrees with VPS35 Mutations Individual pedigrees are labeled and numbered according to their geographic origin (CH, Switzerland; US, United States; TN, Tunisia; YE, Yemenite Jews from Israel). An asterisk indicates an inferred mutation carrier. Filled symbols indicate affected individuals, and the corresponding age at disease onset is indicated; na, not available. Heterozygote mutation carriers (M) and wild-type (wt) genotypes are indicated. (A) Original family used for exome sequencing and identification of VPS35 p.Asp620Asn. (B) Additional kindreds presenting VPS35 p.Asp620Asn mutations. (C) Pedigree presenting the p.Pro316Ser variant.

Figure 2

VPS35 Mutations and Cross-species Conservation Protein orthologs were aligned via ClustalW. Amino acid positions for VPS35 p.Pro316Ser and p.Asp620Asn are highlighted in black. Protein orthologs with amino acid positions differing from those of the human sequence are indicated in gray. RefSeq accession numbers: Homo sapiens, NP_060676.2; Pan troglodytes, XP_001161439.1; Mus musculus, NP_075373.1; Rattus norvegicus, XP_214646.3; Bos taurus, NP_001039723.1; Canis familiaris, XP_532570.2; Gallus gallus, NP_001005842.1; Xenopus laevis, NP_001089981.1; Danio rerio, NP_001020688.2; Drosophila melanogaster, NP_726175.3; and Saccharomyces cerevisiae, NP_012381.1. An asterisk indicates that five aminoacids have been excluded from Drosophila melanogaster and Saccharomyces cerevisiae at this position.