Oliver, VF and Van Bysterveldt, KA and Cadzow, M and Steger, B and Romano, V and Markie, D and Hewitt, AW and Mackey, DA and Willoughby, CE and Sherwin, T and Crosier, PS and McGhee, CN and Vincent, AL, A COL17A1 splice-altering mutation is prevalent in inherited recurrent corneal erosions, Ophthalmology, 123, (4) pp. 709-722. ISSN 0161-6420 (2016) [Refereed Article]
Copyright 2016 American Academy of Ophthalmology Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/
DESIGN: Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.
PARTICIPANTS: Four ERED families, including 28 affected and 17 unaffected individuals.
METHODS: HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle-niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.
MAIN OUTCOME MEASURES: Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.
RESULTS: Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562-112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ-TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.
CONCLUSIONS: The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.
|Item Type:||Refereed Article|
|Research Division:||Medical and Health Sciences|
|Research Group:||Ophthalmology and Optometry|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Hearing, Vision, Speech and Their Disorders|
|UTAS Author:||Hewitt, AW (Professor Alex Hewitt)|
|UTAS Author:||Mackey, DA (Professor David Mackey)|
|Web of Science® Times Cited:||13|
|Deposited By:||Menzies Institute for Medical Research|
|Downloads:||120 View Download Statistics|
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