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MCOLN1 encodes the lysosomal cation channel mucolipin-1. Lisch epithelial corneal dystrophy (LECD) is an autosomal dominant condition characterized by superficial corneal epithelial opacities and autofluorescent lysosomal inclusions (Lisch epithelial corneal dystrophy). Although biallelic MCOLN1 variants cause systemic mucolipidosis type IV (MLIV), heterozygous loss-of-function had not been linked to isolated corneal disease until recently.
In a multicenter cohort of 27 individuals (PMID:37972748) from 17 families (PMID:37972748), nine (PMID:37972748) rare heterozygous MCOLN1 variants were identified in 23 (PMID:37972748) of 27 probands. This included 7 (PMID:37972748) affected members of the original LECD pedigree, 6 (PMID:37972748) patients from two additional families, and 14 (PMID:37972748) simplex cases. Segregation of heterozygous variants occurred in 13 (PMID:37972748) families, confirming autosomal dominant transmission.
Variable expressivity and reduced penetrance are underscored by six obligate MCOLN1 carriers of MLIV-associated genotypes who remain asymptomatic for LECD. Phenotypically, LECD is restricted to the corneal epithelium, with punctate opacities mapped to HP:0007957, and lacks systemic neurologic or gastric involvement seen in MLIV.
The variant spectrum is dominated by truncating alleles—such as c.327C>G (p.Tyr109Ter)—and splice-site changes. Functional assays confirmed that both truncating and a missense variant lead to reduced MCOLN1 function, supporting a haploinsufficiency mechanism (PMID:37972748).
These data establish MCOLN1 haploinsufficiency as the principal cause of LECD. Diagnostic sequencing panels for corneal dystrophies should include MCOLN1 to enable early identification. Future studies to define penetrance modifiers and develop targeted interventions are needed.
Key take-home: Heterozygous loss-of-function MCOLN1 variants cause autosomal dominant LECD through haploinsufficiency with variable expressivity, informing genetic diagnosis and guiding therapeutic research.
Gene–Disease AssociationStrong23 probands across 13 families with segregating heterozygous loss-of-function variants ([PMID:37972748]); functional data confirm haploinsufficiency Genetic EvidenceStrongNine loss-of-function variants in 23 unrelated affected individuals; autosomal dominant inheritance with segregation in 13 families ([PMID:37972748]) Functional EvidenceModerateFunctional assays demonstrate truncating and a missense variant impair MCOLN1 channel function, consistent with haploinsufficiency ([PMID:37972748]) |