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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064165%3A_____%2F24%3A10474140" target="_blank" >RIV/00064165:_____/24:10474140 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11110/24:10474140

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=rxqGfXUmoO" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=rxqGfXUmoO</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ajo.2023.10.011" target="_blank" >10.1016/j.ajo.2023.10.011</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30207 - Ophthalmology

Projekt

—

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

American Journal of Ophthalmology

ISSN

0002-9394

e-ISSN

1879-1891

Svazek periodika

258

Číslo periodika v rámci svazku

February

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

13

Strana od-do

183-195

Kód UT WoS článku

001138113600001

EID výsledku v databázi Scopus

2-s2.0-85180108173