VPS13C – Young-onset Parkinson disease

VPS13C (HGNC:23594) encodes a lipid transfer protein localized to endolysosomal and ER membranes. Young-onset Parkinson disease (MONDO:0017279) is an autosomal recessive neurodegenerative disorder characterized by early bradykinesia, resting tremor, and rigidity.

Multiple sequencing studies in young-onset cohorts have identified biallelic VPS13C variants in affected individuals. Whole genome sequencing of 90 Indian patients found monogenic variants in VPS13C in 1 proband (8.8% overall pathogenic yield) (PMID:35810474). A Chinese exome series of 669 early-onset PD cases reported 7 compound heterozygous carriers (1.05%) with at least one protein-truncating allele (PMID:32507414). Two additional unrelated early-onset cases carrying novel homozygous or compound heterozygous VPS13C mutations were described with diffuse Lewy body pathology (PMID:34875562).

Segregation analysis is limited but includes a consanguineous sib pair with early-onset PD demonstrating recessive inheritance of VPS13C alleles in two affected relatives (PMID:33579389). No pathogenic heterozygotes were symptomatic, supporting autosomal recessive transmission.

Functional assays demonstrate loss-of-function as the pathogenic mechanism. Patient lymphoblasts with compound missense variants showed a 90% reduction in VPS13C expression and mislocalization from endolysosomes (PMID:33579389). VPS13C‐depleted HeLa cells accumulate abnormal lysosomes, exhibit altered lipid profiles including di-22:6-BMP, and activate cGAS-STING signaling due to impaired lysosomal STING degradation, linking VPS13C deficiency to PD pathophysiology (PMID:35657605).

No studies to date have refuted the VPS13C–young-onset PD association. Common variant burden analyses in late-onset cohorts showed no significant enrichment, consistent with a recessive, early-onset phenotype.

Collectively, VPS13C has moderate clinical validity for young-onset Parkinson disease, with multiple unrelated probands, recessive segregation, and concordant functional data. Key Take-home: Biallelic VPS13C loss-of-function mutations cause autosomal recessive young-onset Parkinson disease via impaired lipid transfer and lysosomal dysfunction, informing genetic diagnosis and potential pathway-targeted therapies.

References

• Advanced biology • 2022 • Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India PMID:35810474
• Neurobiology of aging • 2020 • Mutation screening and burden analysis of VPS13C in Chinese patients with early-onset Parkinson's disease PMID:32507414
• Acta neuropathologica communications • 2021 • Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson's disease PMID:33579389
• Parkinsonism & related disorders • 2022 • VPS13C-associated Parkinson's disease: Two novel cases and review of the literature PMID:34875562
• The Journal of cell biology • 2022 • ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling PMID:35657605

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