Rare Heterozygous Loss‐of‐Function Variants in
MCOLN1
Identified in Two Sporadic Patients with
α
Chenxin Ying, Xinhui Chen, Zhidong Cen, Xinghua Feng, Nan Jin, Jiaxiang Li, Xinchen Wang, Wei Luo Abstract
Background
Growing evidence links lysosomal dysfunction to parkinsonism. TRPML1, a lysosomal cation channel encoded by the MCOLN1 gene, is essential for lysosomal function. Biallelic loss‐of‐function variants in MCOLN1 cause mucolipidosis type IV. However, the role of heterozygous MCOLN1 variants remains unclear.
Methods
Two patients with α‐synucleinopathies underwent clinical evaluation and whole‐genome sequencing. The functional effects of TRPML1 variants were assessed using immunofluorescence, lysosomal patch‐clamp recording, and autophagic flux assay.
Results
Two heterozygous MCOLN1 variants were identified: p.E376K in a patient with multiple system atrophy and p.L315del in a patient with early‐onset Parkinson's disease. Functional analyses showed that p.L315del disrupted lysosomal localization, and both variants significantly reduced lysosomal currents upon TRPML1 agonist stimulation, with a trend toward impaired autophagic flux, indicating loss of function.
Conclusions
These findings demonstrate that both variants impair TRPML1 function in vitro, identifying MCOLN1 as a candidate gene for α‐synucleinopathies that warrants further investigation in larger cohorts. © 2026 International Parkinson and Movement Disorder Society.