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Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1
K. Patterson, JX. Chong, DD. Chung, W. Lisch, CL. Karp, E. Dreisler, D. Lockington, JM. Rohrbach, D. Garczarczyk-Asim, T. Müller, SJ. Tuft, P. Skalicka, Y. Wilnai, NN. Samra, A. Ibrahim, H. Mandel, AE. Davidson, P. Liskova, AJ. Aldave, MJ....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu multicentrická studie, časopisecké články
Grantová podpora
MR/S031820/1
Medical Research Council - United Kingdom
- MeSH
- dědičné dystrofie rohovky * diagnóza genetika MeSH
- kationtové kanály TRP * genetika MeSH
- kohortové studie MeSH
- lidé MeSH
- mukolipidózy * diagnóza genetika patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
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.
Department of Pediatrics 1 Medical University of Innsbruck 6020 Innsbruck Austria
Division of Human Genetics Medical University of Innsbruck 6020 Innsbruck Austria
From the Department of Genome Sciences University of Washington Seattle WA 98195 USA
Genetic Institute Tel Aviv Sourasky Medical Center Tel Aviv 6423906 Israel
Genetic Unit Sieff hospital Bar Ilan University Faculty of Medicine Safed Israel
Independent scholar N Jespersensvej 3 DK 2000 Copenhagen Frederiksberg Denmark
Moorfields eye hospital NHS foundation trust London UK
Pediatric Metabolic Clinic Sieff hospital Bar Ilan University Faculty of Medicine Safed Israel
UCL Institute of Ophthalmology 11 43 Bath Street London EC1V 9EL UK
Universitäts Augenklinik Elfriede Aulhorn Str 7 72076 Tübingen Deutschland
Citace poskytuje Crossref.org
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- $a Patterson, Karynne $u From the Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA (K.P., M.J.B.)
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- $a Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1 / $c K. Patterson, JX. Chong, DD. Chung, W. Lisch, CL. Karp, E. Dreisler, D. Lockington, JM. Rohrbach, D. Garczarczyk-Asim, T. Müller, SJ. Tuft, P. Skalicka, Y. Wilnai, NN. Samra, A. Ibrahim, H. Mandel, AE. Davidson, P. Liskova, AJ. Aldave, MJ. Bamshad, AR. Janecke
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- $a 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.
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