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Updated: Aug 7, 2026
09:34
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Rare Heterozygous Loss-of-Function Variants in MCOLN1 Identified in Two Sporadic Patients with α-Synucleinopathies
Chenxin Ying1, Xinhui Chen1, Zhidong Cen1
1Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Summary
Heterozygous variants in the MCOLN1 gene impair TRPML1 channel function, suggesting a potential role for MCOLN1 in alpha-synucleinopathies like Parkinson's disease.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Lysosomal dysfunction is increasingly linked to parkinsonism.
- TRPML1 (encoded by MCOLN1) is a crucial lysosomal cation channel.
- The impact of heterozygous MCOLN1 variants on neurodegenerative diseases is unknown.
Purpose of the Study:
- To investigate the role of heterozygous MCOLN1 variants in alpha-synucleinopathies.
- To assess the functional consequences of identified MCOLN1 variants.
Main Methods:
- Clinical evaluation and whole-genome sequencing of two alpha-synucleinopathy patients.
- Functional assessment of TRPML1 variants using immunofluorescence, lysosomal patch-clamp, and autophagic flux assays.
Main Results:
- Two heterozygous MCOLN1 variants (p.E376K, p.L315del) were found in patients with multiple system atrophy and early-onset Parkinson's disease.
- p.L315del impaired lysosomal localization; both variants reduced TRPML1 currents and showed a trend towards impaired autophagic flux, indicating loss of function.
Conclusions:
- Identified MCOLN1 variants impair TRPML1 function in vitro.
- MCOLN1 is a potential candidate gene for alpha-synucleinopathies, requiring further study in larger patient cohorts.
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