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Lisch epithelial corneal dystrophy is caused by heterozygous loss-of-function variants in MCOLN1

Patterson, K; Chong, JX; Chung, DD; Lisch, L; Møller, HU; Karp, CL; Dreisler, E; ... Janecke, AR; + view all (2024) Lisch epithelial corneal dystrophy is caused by heterozygous loss-of-function variants in MCOLN1. American Journal of Ophthalmology , 258 pp. 183-195. 10.1016/j.ajo.2023.10.011. Green open access

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Abstract

Purpose: To report the genetic etiology of Lisch epithelial corneal dystrophy (LECD). Design: 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.

Type: Article
Title: Lisch epithelial corneal dystrophy is caused by heterozygous loss-of-function variants in MCOLN1
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ajo.2023.10.011
Publisher version: https://doi.org/10.1016/j.ajo.2023.10.011
Language: English
Additional information: Copyright © 2023 The Author(s). This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10179980
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