Genetic variability of the retromer cargo recognition complex in parkinsonism

Background: A pathogenic mutation (VPS35 p.D620N) within the retromer complex has been shown to segregate with late-onset Parkinson's disease (PD). Several studies have subsequently detected the mutation in patients with PD and not in controls. Methods: Mutation screening of the coding regions of the retromer cargo recognition complex genes (VPS26A/B, VPS29, and VPS35) was carried out in patients with PD (n=396), atypical parkinsonism (n=229), and in 368 controls. Results: Overall, we identified five rare nonsynonymous mutations in VPS26A and one in VPS35; none were observed in VPS26B or VPS29. Three VPS26A variants (p.K93E, p.M112V, and p.K297X), identified in patients with atypical parkinsonism, were not observed in controls from this study (n=368) or from publically available data sets (n=4,426). Conclusion: Our results support the hypothesis that rare variants in the retromer complex genes may be involved in the development of parkinsonism, although further studies are warranted before any solid conclusions can be drawn.