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

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

doi:10.1016/j.ajo.2023.10.011

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

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

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English
Pages (from-to)	183-195
Number of pages	13
Journal	American Journal of Ophthalmology
Volume	258
DOIs	https://doi.org/10.1016/j.ajo.2023.10.011
State	Published - Feb 2024

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

Acknowledgements and Financial Disclosure, Funding/Support: Sequencing and analysis of families LECD1, LECD2, and LECD16 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and Center for Rare Disease Research (UW-CRDR) and funded by National Human Genome Research Institute (NHGRI) grant U01 HG011744 and NHGRI and National Heart, Lung, and Blood Institute (NHLBI) grants UM1 HG006493 and U24 HG008956 and by the Office of the Director, National Institutes of Health (NIH) under award number S10OD021553. Alice E. Davidson is funded by a UK Research and Innovation Future Leaders Fellowship MR/S031820/1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the National Health Service (NHS), the National Institute for Health and Care Research, or the UK Department of Health. Financial Disclosures: Petra Liskova was supported by UNCE/MED/007 and SVV 260631. Carol L. Karp has a pending PCT/US2022/029842 with the University of Miami; is on the medical advisory board for Interfeen Biologics; and has received the following institutional funding: NIH Center Core Grant P30EY014801, The RPB Unrestricted Award and Career Development Awards, Dr. Ronald and Alicia Lepke Grant, The Lee and Claire Hager Grant, The Grant and Diana Stanton-Thornbrough, The Robert Baer Family Grant, The Emilyn Page and Mark Feldberg Grant, The Robert Farr Family Grant, The Jose Ferreira de Melo Grant, Mr. and Mrs. Irwin Friedman Grant, The Roberto and Antonia Menendez Family Grant, The Stephen Takach Grant, The Richard and Kathy Lesser Grant, The Ragheb Family Grant, The Honorable A. Jay Cristol Grant, The Michele and Ted Kaplan Grant, The Christian Kathke Grant, The Carol Soffer Grant, and the Richard Azar Family Grant. Anthony J. Aldave has received an unrestricted grant from Research to Prevent Blindness (Stein Eye Institute). All authors attest that they meet the current ICMJE criteria for authorship. Funding/Support: Sequencing and analysis of families LECD1, LECD2, and LECD16 was provided by the University of Washington Center for Mendelian Genomics (UW-CMG) and Center for Rare Disease Research (UW-CRDR) and funded by National Human Genome Research Institute (NHGRI) grant U01 HG011744 and NHGRI and National Heart, Lung, and Blood Institute (NHLBI) grants UM1 HG006493 and U24 HG008956 and by the Office of the Director, National Institutes of Health (NIH) under award number S10OD021553. Alice E. Davidson is funded by a UK Research and Innovation Future Leaders Fellowship MR/S031820/1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the National Health Service (NHS), the National Institute for Health and Care Research, or the UK Department of Health. Financial Disclosures: Petra Liskova was supported by UNCE/MED/007 and SVV 260631. Carol L. Karp has a pending PCT/US2022/029842 with the University of Miami; is on the medical advisory board for Interfeen Biologics; and has received the following institutional funding: NIH Center Core Grant P30EY014801, The RPB Unrestricted Award and Career Development Awards, Dr. Ronald and Alicia Lepke Grant, The Lee and Claire Hager Grant, The Grant and Diana Stanton-Thornbrough, The Robert Baer Family Grant, The Emilyn Page and Mark Feldberg Grant, The Robert Farr Family Grant, The Jose Ferreira de Melo Grant, Mr. and Mrs. Irwin Friedman Grant, The Roberto and Antonia Menendez Family Grant, The Stephen Takach Grant, The Richard and Kathy Lesser Grant, The Ragheb Family Grant, The Honorable A. Jay Cristol Grant, The Michele and Ted Kaplan Grant, The Christian Kathke Grant, The Carol Soffer Grant, and the Richard Azar Family Grant. Anthony J. Aldave has received an unrestricted grant from Research to Prevent Blindness (Stein Eye Institute). All authors attest that they meet the current ICMJE criteria for authorship.

Funders	Funder number
Center for Rare Disease Research
Diana Stanton-Thornbrough
National Health Service
UK Research and Innovation Future Leaders Fellowship	MR/S031820/1
UW-CRDR
National Institutes of Health	S10OD021553
National Heart, Lung, and Blood Institute	UM1 HG006493, U24 HG008956
National Human Genome Research Institute	U01 HG011744
Office of the Director
Research to Prevent Blindness
University of Miami	P30EY014801
Center for Mendelian Genomics, University of Washington
National Institute for Health and Care Research	SVV 260631, UNCE/MED/007

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10.1016/j.ajo.2023.10.011

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Patterson, K., Chong, J. X., Chung, D. D., Lisch, W., Karp, C. L., Dreisler, E., Lockington, D., Rohrbach, J. M., Garczarczyk-Asim, D., Müller, T., Tuft, S. J., Skalicka, P., Wilnai, Y., Samra, N. N., Ibrahim, A., Mandel, H., Davidson, A. E., Liskova, P., Aldave, A. J., ... Janecke, A. R. (2024). Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1. American Journal of Ophthalmology, 258, 183-195. https://doi.org/10.1016/j.ajo.2023.10.011

@article{98ecba1961a0434e96b0aa2a04289f42,

title = "Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2024",

month = feb,

doi = "10.1016/j.ajo.2023.10.011",

language = "אנגלית",

volume = "258",

pages = "183--195",

journal = "American Journal of Ophthalmology",

issn = "0002-9394",

publisher = "Elsevier Inc.",

}

Patterson, K, Chong, JX, Chung, DD, Lisch, W, Karp, CL, Dreisler, E, Lockington, D, Rohrbach, JM, Garczarczyk-Asim, D, Müller, T, Tuft, SJ, Skalicka, P, Wilnai, Y, Samra, NN, Ibrahim, A, Mandel, H, Davidson, AE, Liskova, P, Aldave, AJ, Bamshad, MJ & Janecke, AR 2024, 'Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1', American Journal of Ophthalmology, vol. 258, pp. 183-195. https://doi.org/10.1016/j.ajo.2023.10.011

TY - JOUR

T1 - Lisch Epithelial Corneal Dystrophy Is Caused by Heterozygous Loss-of-Function Variants in MCOLN1

AU - Patterson, Karynne

AU - Chong, Jessica X.

AU - Chung, Doug D.

AU - Lisch, Walter

AU - Karp, Carol L.

AU - Dreisler, Erling

AU - Lockington, David

AU - Rohrbach, Jens M.

AU - Garczarczyk-Asim, Dorota

AU - Müller, Thomas

AU - Tuft, Stephen J.

AU - Skalicka, Pavlina

AU - Wilnai, Yael

AU - Samra, Nadra Naser

AU - Ibrahim, Ali

AU - Mandel, Hanna

AU - Davidson, Alice E.

AU - Liskova, Petra

AU - Aldave, Anthony J.

AU - Bamshad, Michael J.

AU - Janecke, Andreas R.

PY - 2024/2

Y1 - 2024/2

N2 - 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.

AB - 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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ER -

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

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