A COL17A1 splice-altering mutation is prevalent in inherited recurrent corneal erosions

<strong>PURPOSE:</strong> Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.<p></p> <p><strong>DESIGN:</strong> 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.</p> <p><strong>PARTICIPANTS:</strong> Four ERED families, including 28 affected and 17 unaffected individuals.</p> <p><strong>METHODS:</strong> 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.</p> <p><strong>MAIN OUTCOME MEASURES:</strong> Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.</p> <p><strong>RESULTS:</strong> 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: <i>COL17A1</i> c.3156C→T and <i>DNAJC9</i> c.334G→A. The <i>COL17A1</i> 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 <i>Col17a1a</i> and <i>Dnajc9</i> during development show no gross corneal phenotype.</p> <p><strong>CONCLUSIONS:</strong> The <i>COL17A1</i> 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 <i>COL17A1</i> c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of <i>COL17A1</i> disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies <i>COL17A1</i> as a key protein in maintaining integrity of the corneal epithelium.</p>