Biomaterial Database

Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1. 2024

Karynne Patterson, and Jessica X Chong, and Doug D Chung, and Walter Lisch, and Carol L Karp, and Erling Dreisler, and David Lockington, and Jens M Rohrbach, and Dorota Garczarczyk-Asim, and Thomas Müller, and Stephen J Tuft, and Pavlina Skalicka, and Yael Wilnai, and Nadra Naser Samra, and Ali Ibrahim, and Hanna Mandel, and Alice E Davidson, and Petra Liskova, and Anthony J Aldave, and Michael J Bamshad, and Andreas R Janecke

From the Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA (K.P., M.J.B.).

OBJECTIVE To report the genetic etiology of Lisch epithelial corneal dystrophy (LECD). METHODS Multicenter cohort study. METHODS A discovery cohort of 27 individuals with LECD from 17 families, including 7 affected members from the original LECD family, 6 patients from 2 new families and 14 simplex cases, was recruited. A cohort of 6 individuals carrying a pathogenic MCOLN1 (mucolipin 1) variant was reviewed for signs of LECD. Next-generation sequencing or targeted Sanger sequencing were used in all patients to identify pathogenic or likely pathogenic variants and penetrance of variants. RESULTS Nine rare heterozygous MCOLN1 variants were identified in 23 of 27 affected individuals from 13 families. The truncating nature of 7 variants and functional testing of 1 missense variant indicated that they result in MCOLN1 haploinsufficiency. Importantly, in the homozygous and compound-heterozygous state, 4 of 9 LECD-associated variants cause the rare lysosomal storage disorder mucolipidosis IV (MLIV). Autosomal recessive MLIV is a systemic disease and comprises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. However, the 6 parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype, suggesting MCOLN1 haploinsufficiency may be associated with reduced penetrance and variable expressivity. CONCLUSIONS MCOLN1 haploinsufficiency is the major cause of LECD. Based on the overlapping clinical features of corneal epithelial cells with autofluorescent inclusions reported in both LECD and MLIV, it is concluded that some carriers of MCOLN1 haploinsufficiency-causing variants present with LECD.

UI	MeSH Term	Description	Entries
D009081	Mucolipidoses	A group of inherited metabolic diseases characterized by the accumulation of excessive amounts of acid mucopolysaccharides, sphingolipids, and/or glycolipids in visceral and mesenchymal cells. Abnormal amounts of sphingolipids or glycolipids are present in neural tissue. INTELLECTUAL DISABILITY and skeletal changes, most notably dysostosis multiplex, occur frequently. (From Joynt, Clinical Neurology, 1992, Ch56, pp36-7)	Cherry Red Spot Myoclonus Syndrome,Ganglioside Sialidase Deficiency Disease,I-Cell Disease,Lipomucopolysaccharidosis,Mucolipidosis,Myoclonus Cherry Red Spot Syndrome,Pseudo-Hurler Polydystrophy,Sialidosis,Cherry Red Spot-Myoclonus Syndrome,Deficiency Disease, Ganglioside Sialidase,Glycoprotein Neuraminidase Deficiency,Inclusion Cell Disease,Mucolipidosis I,Mucolipidosis II,Mucolipidosis III,Mucolipidosis III Alpha Beta,Mucolipidosis IIIa,Mucolipidosis IV,Mucolipidosis Type 1,Mucolipidosis Type I,Mucolipidosis Type II,Mucolipidosis Type III,Mucolipidosis Type IV,Myoclonus-Cherry Red Spot Syndrome,Psuedo-Hurler Disease,Sialolipidosis,Type I Mucolipidosis,Type II Mucolipidosis,Type III Mucolipidosis,Type IV Mucolipidosis,Deficiencies, Glycoprotein Neuraminidase,Deficiency, Glycoprotein Neuraminidase,Glycoprotein Neuraminidase Deficiencies,I Cell Disease,I-Cell Diseases,Inclusion Cell Diseases,Lipomucopolysaccharidoses,Mucolipidoses, Type I,Mucolipidoses, Type II,Mucolipidoses, Type III,Mucolipidoses, Type IV,Mucolipidosis, Type I,Mucolipidosis, Type II,Mucolipidosis, Type III,Mucolipidosis, Type IV,Polydystrophy, Pseudo-Hurler,Pseudo Hurler Polydystrophy,Psuedo Hurler Disease,Psuedo-Hurler Diseases,Sialidoses,Sialolipidoses,Type I Mucolipidoses,Type II Mucolipidoses,Type III Mucolipidoses,Type IV Mucolipidoses
D003317	Corneal Dystrophies, Hereditary	Bilateral hereditary disorders of the cornea, usually autosomal dominant, which may be present at birth but more frequently develop during adolescence and progress slowly throughout life. Central macular dystrophy is transmitted as an autosomal recessive defect.	Corneal Dystrophies,Granular Dystrophy, Corneal,Groenouw's Dystrophies,Macular Dystrophy, Corneal,Stromal Dystrophies, Corneal,Corneal Dystrophy,Corneal Dystrophy, Hereditary,Corneal Granular Dystrophies,Corneal Granular Dystrophy,Corneal Macular Dystrophies,Corneal Macular Dystrophy,Corneal Stromal Dystrophies,Corneal Stromal Dystrophy,Dystrophy, Corneal,Dystrophy, Corneal Granular,Dystrophy, Corneal Macular,Dystrophy, Corneal Stromal,Dystrophy, Hereditary Corneal,Groenouw Dystrophies,Groenouws Dystrophies,Hereditary Corneal Dystrophies,Hereditary Corneal Dystrophy,Stromal Dystrophy, Corneal
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015331	Cohort Studies	Studies in which subsets of a defined population are identified. These groups may or may not be exposed to factors hypothesized to influence the probability of the occurrence of a particular disease or other outcome. Cohorts are defined populations which, as a whole, are followed in an attempt to determine distinguishing subgroup characteristics.	Birth Cohort Studies,Birth Cohort Study,Closed Cohort Studies,Cohort Analysis,Concurrent Studies,Historical Cohort Studies,Incidence Studies,Analysis, Cohort,Cohort Studies, Closed,Cohort Studies, Historical,Studies, Closed Cohort,Studies, Concurrent,Studies, Historical Cohort,Analyses, Cohort,Closed Cohort Study,Cohort Analyses,Cohort Studies, Birth,Cohort Study,Cohort Study, Birth,Cohort Study, Closed,Cohort Study, Historical,Concurrent Study,Historical Cohort Study,Incidence Study,Studies, Birth Cohort,Studies, Cohort,Studies, Incidence,Study, Birth Cohort,Study, Closed Cohort,Study, Cohort,Study, Concurrent,Study, Historical Cohort,Study, Incidence
D050051	Transient Receptor Potential Channels	A broad group of eukaryotic six-transmembrane cation channels that are classified by sequence homology because their functional involvement with SENSATION is varied. They have only weak voltage sensitivity and ion selectivity. They are named after a DROSOPHILA mutant that displayed transient receptor potentials in response to light. A 25-amino-acid motif containing a TRP box (EWKFAR) just C-terminal to S6 is found in TRPC, TRPV and TRPM subgroups. ANKYRIN REPEATS are found in TRPC, TRPV & TRPN subgroups. Some are functionally associated with TYROSINE KINASE or TYPE C PHOSPHOLIPASES.	TRP Cation Channel,Transient Receptor Potential Cation Channel,Transient Receptor Potential Channel,TRP Cation Channels,TRP Membrane Proteins,Transient Receptor Potential Cation Channels,Cation Channel, TRP,Cation Channels, TRP,Channel, TRP Cation,Channels, TRP Cation,Membrane Proteins, TRP,Proteins, TRP Membrane