title: Mutations in collagen, type XVII, alpha 1 (COL17A1) cause epithelial recurrent erosion dystrophy (ERED).
abstract: Corneal dystrophies are a clinically and genetically heterogeneous group of inherited disorders that bilaterally affect corneal transparency. They are defined according to the corneal layer affected and by their genetic cause. In this study, we identified a dominantly inherited epithelial recurrent erosion dystrophy (ERED)-like disease that is common in northern Sweden. Whole-exome sequencing resulted in the identification of a novel mutation, c.2816C>T, p.T939I, in the COL17A1 gene, which encodes collagen type XVII alpha 1. The variant segregated with disease in a genealogically expanded pedigree dating back 200 years. We also investigated a unique COL17A1 synonymous variant, c.3156C>T, identified in a previously reported unrelated dominant ERED-like family linked to a locus on chromosome 10q23-q24 encompassing COL17A1. We show that this variant introduces a cryptic donor site resulting in aberrant pre-mRNA splicing and is highly likely to be pathogenic. Bi-allelic COL17A1 mutations have previously been associated with a recessive skin disorder, junctional epidermolysis bullosa, with recurrent corneal erosions being reported in some cases. Our findings implicate presumed gain-of-function COL17A1 mutations causing dominantly inherited ERED and improve understanding of the underlying pathology.
authors: Department of Medical Biosciences/Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
authors: Frida
authors: F
authors: Jonsson
authors: Berit
authors: B
authors: Byström
authors: Alice E
authors: AE
authors: Davidson
authors: Ludvig J
authors: LJ
authors: Backman
authors: Therese G
authors: TG
authors: Kellgren
authors: Stephen J
authors: SJ
authors: Tuft
authors: Timo
authors: T
authors: Koskela
authors: Patrik
authors: P
authors: Rydén
authors: Ola
authors: O
authors: Sandgren
authors: Patrik
authors: P
authors: Danielson
authors: Alison J
authors: AJ
authors: Hardcastle
authors: Irina
authors: I
authors: Golovleva
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D002648:Child; D003317:Corneal Dystrophies, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D019573:Epithelium, Corneal / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D024041:Non-Fibrillar Collagens / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012326:RNA Splicing; D055815:Young Adult; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII
keywords: BP180; COL17A1; ERED; cornea dystrophy; ddPCR