title: Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy.
abstract: Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial dystrophies, leading to corneal opacification. This group of conditions includes Fuchs' endothelial dystrophy of the cornea (FECD), one of the commonest indications for corneal transplantation performed in developed countries, posterior polymorphous dystrophy (PPCD) and the congenital hereditary endothelial dystrophies (CHED). A genome-wide search of a three-generation family with early-onset FECD demonstrated significant linkage with D1S2830 (Z(max) = 3.72, theta = 0.0). Refinement of the critical region defined a 6-7 cM interval of chromosome 1p34.3-p32 within which lies the COL8A2 gene. This encodes the 703 amino acid alpha2 chain of type VIII collagen, a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD. This is the first description of the molecular basis of any of the corneal endothelial dystrophies or of mutations in type VIII collagen in association with human disease. This suggests that the underlying pathogenesis of FECD and PPCD may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest derived corneal endothelial cell.
authors.affiliation: Academic Department of Ophthalmology, Manchester Royal Eye Hospital, Oxford Road, Manchester M13 9WH, UK.
authors.forename: S
authors.initials: S
authors.lastname: Biswas
authors.forename: F L
authors.initials: FL
authors.lastname: Munier
authors.forename: J
authors.initials: J
authors.lastname: Yardley
authors.forename: N
authors.initials: N
authors.lastname: Hart-Holden
authors.forename: R
authors.initials: R
authors.lastname: Perveen
authors.forename: P
authors.initials: P
authors.lastname: Cousin
authors.forename: J E
authors.initials: JE
authors.lastname: Sutphin
authors.forename: B
authors.initials: B
authors.lastname: Noble
authors.forename: M
authors.initials: M
authors.lastname: Batterbury
authors.forename: C
authors.initials: C
authors.lastname: Kielty
authors.forename: A
authors.initials: A
authors.lastname: Hackett
authors.forename: R
authors.initials: R
authors.lastname: Bonshek
authors.forename: A
authors.initials: A
authors.lastname: Ridgway
authors.forename: D
authors.initials: D
authors.lastname: McLeod
authors.forename: V C
authors.initials: VC
authors.lastname: Sheffield
authors.forename: E M
authors.initials: EM
authors.lastname: Stone
authors.forename: D F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: G C
authors.initials: GC
authors.lastname: Black
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D024102:Collagen Type VIII / Q000235:genetics*; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004728:Endothelium, Corneal / Q000473:pathology* / Q000648:ultrastructure; D005192:Family Health; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics* / Q000473:pathology; D005796:Genes / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: C443712:COL8A2 protein, human; D024102:Collagen Type VIII; D004247:DNA