Nature Genetics
16, 184 - 187 (1997)
doi:10.1038/ng0697-184
Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophyAlan D. Irvine1, *, Laura D. Corden2, 3, *, Ole Swensson4, Beate Swensson5, Jonathan E. Moore6, David G. Frazer6, Frances J.D. Smith2, Robert G. Knowlton7, Enno Christophers4, Rainer Rochels5, Jouni Uitto7, 8
& W.H. Irwin McLean2, 9
1Department of Dermatology, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK.
2Epithelial Genetics Group, Department of Dermatology and Cutaneous Biology, Jefferson Medical College, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA.
3CRC Cell Structure Research Group, Cancer Research Campaign Laboratories, Department of Anatomy and Physiology, Medical Sciences Institute, University of Dundee DD1 4HN, UK.
4Department of Dermatology, and Christian-Albrechts- Universität, Kiel 24105, Germany.
5Department of Ophthalmology, Christian-Albrechts- Universität, Kiel 24105, Germany.
6Department of Ophthalmology, Royal Group of Hospitals, Grosvenor Road, Belfast BT12 6BA, UK.
7Departments of Dermatology and Cutaneous Biology, and Jefferson Institute of Molecular Medicine, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA.
8Departments of Biochemistry and Molecular Pharmacology, Jefferson Institute of Molecular Medicine, 233 South 10th Street, Philadelphia, Pennsylvania 19107, USA.
9Correspondence should be addressed to W.H.I.M.
*A.D.I. &L.D.C. contributed equally to this work. The intermediate filament cytoskeleton of corneal epithelial cells is composed of cornea-specific keratins K3 and K12 (refs 1,2). Meesmann's corneal dystrophy (MCD) is an autosomal dominant disorder causing fragility of the anterior corneal epithelium3,4, where K3 and K12 are specifically expressed5. We postulated that dominant-negative mutations in these keratins might be the cause of MCD. K3 was mapped to the type-ll keratin gene cluster on 12q; and K12 to the type-l keratin cluster on 17q using radiation hybrids. We obtained linkage to the K12 locus in Meesmann's original German kindred (Zmax=7.53;  =0) and we also showed that the phenotype segregated with either the K12 or the K3 locus in two Northern Irish pedigrees. Heterozygous missense mutations in K3 (E509K) and in K12 (V143L; R135T) completely co-segregated with MCD in the families and were not found in 100 normal unrelated chromosomes. All mutations occur in the highly conserved keratin helix boundary motifs, where dominant mutations in other keratins have been found to severely compromise cytoskeletal function, leading to keratinocyte fragility phenotypes. Our results demonstrate for the first time the molecular basis of Meesmann's corneal dystrophy.
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