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J Biol Chem, Vol. 275, Issue 15, 11465-11469, April 14, 2000
From the 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.
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*
§¶,
,,
, and
Division of Medical Genetics, Lausanne
University Hospital (CHUV), ch. des Falaises 1, CH-1011 Lausanne, Switzerland, the Laboratory of Clinical
Chemistry, Lausanne University Hospital (CHUV),
CH-1011 Lausanne, Switzerland, the ** Department of Ophthalmology,
Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku,
Tokyo, 160-8582, Japan and the Department of
Ophthalmology, Jules Gonin Ophthalmic Hospital, CH-1004
Lausanne, Switzerland
*
This work was supported by Grants 31-052940.97 (to D. F. S.) and 32-58439.99 (Marie Heim-Vögtlin Beiträge,
to E. K.) from the Swiss National Science Foundation and from the
Foundation of the 450th Anniversary of the University of Lausanne (to
E. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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