Objective: To evaluate the association between heterozygous loss-of-function variants in the MCOLN1 gene and α-synucleinopathies.

Background: Lysosomes play a crucial role in cellular waste disposal, and their dysfunction can lead to various diseases. Growing evidence suggests a strong link between lysosomal dysfunction and α-synuclein aggregation in PD and multiple system atrophy (MSA). TRPML1, a lysosomal cation channel encoded by the MCOLN1 gene, is crucial for lysosomal function, and its biallelic loss-of-function mutations cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. However, the relationship between heterozygous MCOLN1 mutations and α-synucleinopathies remains further investigation.

Method: We conducted whole-genome sequencing on patients with early-onset Parkinson’s disease and other α-Synucleinopathies without known genetic variants. To evaluate the functional impact of mutant TRPML1 at the protein level, we performed immunofluorescence analysis and lysorecording.

Results: We identified a heterozygous MCOLN1 variant, c.943_945delCTC (p.L315del), in a male patient with early-onset Parkinson’s disease, who initially presented with bradykinesia in the left limbs at 43 years old. Additionally, we detected another heterozygous variant, c.1126G>A (p.E376K), in a female patient with MSA. She developed bradykinesia in the right limbs at age 55 and was diagnosed with probable MSA-C at 59 years old. Functional assays revealed that the p.L315del mutant TRPML1 failed to localize to lysosomes, while the p.E376K mutant exhibited a dramatic reduction in lysosomal current upon TRPML1 agonist stimulation.

Conclusion: This study identified two rare heterozygous variants in the MCOLN1 gene in patients with α-Synucleinopathies, and functional assays demonstrated that both resulted in a loss of function.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-between-heterozygous-loss-of-function-variants-in-the-mcoln1-gene-and-%ce%b1-synucleinopathies/