VPS35 – Parkinson disease 17

Heterozygous VPS35 c.1858G>A (p.Asp620Asn) underlies autosomal dominant PARK17 ([PMID:21763482]). This variant has been identified in at least 7 probands across 5 unrelated kindreds and 2 sporadic cases, and is absent from >3,000 controls, supporting Mendelian segregation in multiple multi-generation families ([PMID:23125461]).

Genetic evidence demonstrates an autosomal dominant inheritance pattern with co-segregation of p.Asp620Asn in affected relatives and complete absence in controls, fulfilling ClinGen Strong genetic evidence criteria. Additional rare VPS35 missense variants (p.Pro316Ser, p.Leu774Met, p.Gly51Ser) have been reported but lack clear pathogenicity or show limited penetrance across populations ([PMID:21763482], [PMID:23125461]).

Functional studies in heterozygous VPS35D620N/+ knockin mice recapitulate key PARK17 features: late-onset nigrostriatal dopaminergic neuron loss, motor deficits, and impaired Wnt/β-catenin signaling with reduced Wnt1, nuclear β-catenin, and survivin levels alongside caspase activation ([PMID:33257649]). In Drosophila, D620N expression induces age-dependent TH+ neuron loss and locomotor defects, whereas L774M shows no pathogenicity, confirming variant-specific neurotoxicity ([PMID:25288323]).

Cellular assays reveal that VPS35 deficiency or D620N mutation disrupts endosome-to-Golgi retrieval of Lamp2a, leading to α-synuclein accumulation and DA neuron loss, and increases MUL1-mediated MFN2 degradation with resultant mitochondrial fragmentation and dysfunction ([PMID:26203154], [PMID:26321632]).

Mechanistic evidence indicates a gain-of-function/partial loss-of-function effect: VPS35[D620N] enhances LRRK2-mediated Rab10 phosphorylation, hyperactivating kinase pathways implicated in PD, offering rationale for LRRK2 inhibitor therapy ([PMID:29743203]).

Collectively, VPS35 p.Asp620Asn meets ClinGen Definitive criteria with robust genetic segregation, multiple independent replication, and concordant in vivo and cellular functional data. Genetic testing for VPS35 D620N informs diagnosis and may guide emerging retromer- and LRRK2-targeted therapies.

References

• American journal of human genetics • 2011 • VPS35 mutations in Parkinson disease. PMID:21763482
• Journal of medical genetics • 2012 • A multi-centre clinico-genetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. PMID:23125461
• Cell death & disease • 2020 • (D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model PMID:33257649
• Molecular brain • 2014 • In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila. PMID:25288323
• The Journal of neuroscience • 2015 • VPS35 in Dopamine Neurons Is Required for Endosome-to-Golgi Retrieval of Lamp2a, a Receptor of Chaperone-Mediated Autophagy That Is Critical for α-Synuclein Degradation and Prevention of Pathogenesis of Parkinson's Disease PMID:26203154
• Cell reports • 2015 • VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function. PMID:26321632
• The Biochemical journal • 2018 • The Parkinson's disease VPS35[D620N] mutation enhances LRRK2-mediated Rab protein phosphorylation in mouse and human. PMID:29743203

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