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

Mutations in kerato-epithelin are responsible for a group of hereditary cor nea-specific deposition diseases, 5q31-linked corneal dystrophies, These co nditions 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-amylo id (R124L), and a mixed pattern of deposition (R124H), We found that aggreg ated kerato-epithelin comprised all types of pathological deposits. Each mu tation was associated with characteristic changes of protein turnover in co rneal tissue. Amyloidogenesis in R124C corneas was accompanied by the accum ulation of N-terminal kerato-epithelin fragments, whereby species of 44 kDa were the major constituents of amyloid fibrils, R124H corneas with prevail ing non-amyloid inclusions showed accumulation of a new 66-kDa species alto gether with the full-size 68-kDa form, Finally, in R124L cornea with non am yloid deposits, we found only the accumulation of the 68-kDa form. Two-dime nsional gels revealed mutation-specific changes in the processing of the fu ll-size protein in all affected corneas, It appears that substitutions at t he same residue (Arg-124) result in cornea-specific deposition of kerato-ep ithelin via distinct aggregation pathways each involving altered turnover o f the protein in corneal tissue.