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Updated: Aug 7, 2026

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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.

Movement Disorders : Official Journal of the Movement Disorder Society
|August 6, 2026
PubMed
Abstract

Insights

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.
Keywords:
MCOLN1Parkinson's diseaseloss of functionmultiple system atrophyα‐synucleinopathies

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