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

Topic: Brain proteins, microglia and lab models

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.

Key findings

• 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.

Why it matters

This study identified a VPS35 mutation causing late-onset Parkinson's disease in an Austrian family and additional families, with a mean age of onset of 53 years. It concerns Parkinson's disease genetics, not Alzheimer's disease, so it does not directly inform Alzheimer's treatment, cure or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.ajhg.2011.06.008
• PubMed: 21763483
• Original source →
• Free full text: The American Journal of Human Genetics →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{zimprich2011-21763483,
  author  = {Zimprich, A. and Benet-Pagès, A. and Struhal, W. and Graf, E. and Eck, S. H. and Offman, M. N. and Haubenberger, D. and Spielberger, S. and others},
  title   = {{A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease}},
  journal = {American journal of human genetics},
  year    = {2011},
  doi     = {10.1016/j.ajhg.2011.06.008},
  pmid    = {21763483},
  url     = {https://doi.org/10.1016/j.ajhg.2011.06.008}
}

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