title: Amyloid and non-amyloid forms of 5q31-linked corneal dystrophy resulting from kerato-epithelin mutations at Arg-124 are associated with abnormal turnover of the protein.
abstract: Mutations in kerato-epithelin are responsible for a group of hereditary cornea-specific deposition diseases, 5q31-linked corneal dystrophies. These conditions are characterized by progressive accumulation of protein deposits of different ultrastructure. Herein, we studied the corneas with mutations at kerato-epithelin residue Arg-124 resulting in amyloid (R124C), non-amyloid (R124L), and a mixed pattern of deposition (R124H). We found that aggregated kerato-epithelin comprised all types of pathological deposits. Each mutation was associated with characteristic changes of protein turnover in corneal tissue. Amyloidogenesis in R124C corneas was accompanied by the accumulation of N-terminal kerato-epithelin fragments, whereby species of 44 kDa were the major constituents of amyloid fibrils. R124H corneas with prevailing non-amyloid inclusions showed accumulation of a new 66-kDa species altogether with the full-size 68-kDa form. Finally, in R124L cornea with non amyloid deposits, we found only the accumulation of the 68-kDa form. Two-dimensional gels revealed mutation-specific changes in the processing of the full-size protein in all affected corneas. It appears that substitutions at the same residue (Arg-124) result in cornea-specific deposition of kerato-epithelin via distinct aggregation pathways each involving altered turnover of the protein in corneal tissue.
authors.affiliation: Division of Medical Genetics, Lausanne University Hospital (CHUV), ch. des Falaises 1, CH-1011 Lausanne, Switzerland. Korvatska@hotmail.com
authors.forename: E
authors.initials: E
authors.lastname: Korvatska
authors.forename: H
authors.initials: H
authors.lastname: Henry
authors.forename: Y
authors.initials: Y
authors.lastname: Mashima
authors.forename: M
authors.initials: M
authors.lastname: Yamada
authors.forename: C
authors.initials: C
authors.lastname: Bachmann
authors.forename: F L
authors.initials: FL
authors.lastname: Munier
authors.forename: D F
authors.initials: DF
authors.lastname: Schorderet
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D002895:Chromosomes, Human, Pair 5; D003315:Cornea / Q000737:chemistry; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics*; D016326:Extracellular Matrix Proteins; D006801:Humans; D008970:Molecular Weight; D009154:Mutation; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D011817:Rabbits; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein
chemical_list: D000682:Amyloid; D016326:Extracellular Matrix Proteins; D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein