The relationship between the MCOLN1 gene and mucolipidosis type IV (ML4), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of September 10, 2022. MCOLN1 encodes mucolipin-1, a cation channel that is involved in lysosomal exocytosis, a calcium-dependent process where endosomes fuse with lysosomes, and then fuse with the plasma membrane, via mediating intracellular calcium concentrations through its role as a calcium channel (PMID: 15336987). Among patients with ML4, impaired mucolipin-1 function results in impaired lysosomal exocytosis (PMID: 16914343), leading to disease manifestations which include neurodegeneration with psychomotor retardation, ophthalmologic anomalies, and achlorhydria (as reviewed in PMID: 32604955, PMID: 21763169, PMID: 12182165).
The disease mechanism of ML4 is loss of function. ML4 was first reported by Berman et al. in 1974 (PMID: 4365943) and the first report of biallelic variants in MCOLN1 among ML4 patients was by Bargal et al. in 2000 (PMID: 10973263). Both case-level (genetic) and experimental evidence support the relationship between MCOLN1 and ML4. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants (PMID: 10973263, PMID: 11030752, PMID: 15523648, PMID: 31899079, PMID: 18326692). In total, eleven variants from six probands in five publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached.
Experimental evidence for the relationship between MCOLN1 and ML4 includes: the biochemical function of the gene product (mucolipin-1) being consistent with the clinical and biochemical findings identified in individuals with ML4 (PMID: 15336987, PMID: 16914343, PMID: 32604955, PMID: 21763169, PMID: 12182165); the biochemical and clinical features of MCOLN1 knockout mice (PMID: 17924347); and rescue of neurologic impairment and neuronal accumulation of undegraded lysosomal substrates via adenovirus -mediated gene therapy in MCOLN1 knockout mice (PMID: 29788236). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached.
In sum, MCOLN1 is definitively associated with ML4. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on September 14, 2022 (SOP v9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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