Objective: To investigate whether heterozygous VPS13C variants modify the phenotype of AARS1-related Charcot-Marie-Tooth disease (CMT) and explore a potential interaction between AARS1 and VPS13C.

Background: AARS1 encodes alanyl-tRNA synthetase, and pathogenic variants cause CMT2N, an autosomal-dominant axonal neuropathy. Increasing evidence suggests that aaRS-related neuropathies arise from gain-of-function mechanisms independent of aminoacylation activity¹. Parkinson’s disease (PD) has been reported years after neuropathy suggestive of CMT2N², and mutations in several CMT genes have been identified in patients who later developed PD^{3, 4}. VPS13C encodes a lysosome-associated lipid transport protein, and loss-of-function variants cause autosomal-recessive early-onset PD through disruption of lysosomal and mitochondrial homeostasis^{5, 6}. However, whether heterozygous VPS13C variants modify AARS1-related disease remains unclear.

Method: Whole-genome sequencing (WGS) was performed in a pedigree in which the proband presented with both CMT and PD, followed by segregation analysis across three generations. Fibroblasts from two affected family members (one with CMT+PD and one with CMT only) were used for protein expression and lysosomal analyses. Lysosomal morphology and pH were assessed using LysoTracker staining and live-cell confocal microscopy. Co-immunoprecipitation assays in an overexpression system evaluated interaction between AARS1 and VPS13C.

Results: The proband carried heterozygous variants in both AARS1 (c.1132G>A) and VPS13C (c.10790C>G). Segregation analysis showed that three individuals with CMT and PD carried both variants, whereas two with CMT alone carried only the AARS1 variant. Western blot of fibroblasts showed reduced VPS13C protein levels in the individual carrying both variants, while AARS1 expression remained comparable to controls. Co-immunoprecipitation suggested reduced interaction between mutant AARS1 and VPS13C, although not statistically significant. Lysosomal pH, morphology, and distribution were unchanged under basal conditions.

Conclusion: Heterozygous VPS13C variants may act as a genetic modifier in individuals with AARS1 mutations and contribute to PD development. Further studies are needed to determine whether VPS13C haploinsufficiency increases susceptibility to lysosomal stress and dopaminergic neurodegeneration.

References: 1. Sun L, Wei N, Kuhle B, et al. CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS. Proc Natl Acad Sci U S A 2021;118.
2. Tranchant C, Ruh D, Warter JM. [Type II Charcot-Marie-Tooth and dopa-sensitive Parkinson disease]. Rev Neurol (Paris) 1994;150:72–74.
3. Aerts MB, Weterman MA, Quadri M, et al. A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson’s disease. Ann Clin Transl Neurol 2016;3:146–149.
4. Lerint AN, Canenguez Benitez JS, Valaparla VL, Shanina E, Wu LJ. Co-Existing Charcot-Marie-Tooth Disease Type II and Parkinson’s Disease Linked to a Novel DNAjB2 Pathogenic Variant. J Cent Nerv Syst Dis 2026;18:11795735261428314.
5. Lesage S, Drouet V, Majounie E, et al. Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. Am J Hum Genet 2016;98:500–513.
6. Schrӧder LF, Peng W, Gao G, Wong YC, Schwake M, Krainc D. VPS13C regulates phospho-Rab10-mediated lysosomal function in human dopaminergic neurons. J Cell Biol 2024;223.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/vps13c-heterozygous-variant-as-a-potential-modifier-in-aars1-related-charcot-marie-tooth-disease-with-parkinsons-disease/