97th DOG Annual Meeting 1999
IDENTIFICATION OF A NOVEL KERATIN 12 GENE MUTATION IN PATIENTS WITH MEESMANN'S CORNEAL DYSTROPHY.
L. D. Corden1, B. Swensson2, B. Wannke3, W. H. I. McLean1, R. Rochels2, H.-J. Thiel3, O. Swensson4
Meesmann's corneal dystrophy (MCD) is an autosomal dominantly inherited disorder of corneal epithelium characterized by punctate intraepithelial vesicles and dot-like epithelial erosions. Using linkage analysis in descendants of the families described by Meesmann and Wilke we could show that the genetic defect of MCD localizes to the keratin (K) gene cluster on chromosome 17 (17q12-21). Using molecular genetic analyses in this MCD family and two unrelated families of Irish descent we identified mutations in both cornea-specific keratin genes K3 and K12 [Nat Genet 16:184-187,1997].
Patients and methods: We investigated a further family with MCD from southern Germany. Seven of eighteen family members spanning three generations showed characteristic clinical signs of the disease. DNA samples were obtained from affected (n=4) and unaffected (n=2) individuals. Genetic linkage analyses were performed using microsatellite markers within the type I and type II keratin gene clusters. The regions encoding the functionally important helix initiation motif of the candidate gene were amplified and directly sequenced.
Results: Using genetic linkage we were able to exclude K3 as a candidate gene. Amplification and direct sequencing of exon 1 of the K12 gene yielded a hitherto unreported heterozygous missense mutation (A413C). All affected individuals were shown to carry this mutation, which predicts a glutamine to proline substitution (Q130P) of the fifth aminoacid of the 1A domain in the highly conserved helix initiation motif of the K12 molecule.
Conclusion: Our findings provide further evidence that pathogenic mutations in cornea-specific keratins seem to represent the underlying genetic defect in patients with MCD. Whether abnormalities of functionally related structural proteins, e.g. desmosomal components, could result in a phenotype similar to the epithelial corneal dystrophy described by Meesmann and Wilke remains to be seen.
1Dept. of Molecular and Cellular Pathology, University of Dundee, Scotland
2Universitäts-Augenklinik Kiel, Hegewischstr. 2, 24105 Kiel
3Universitäts-Augenklinik Tübingen, Schleichstr. 12-16, 72076 Tübingen
4Universitäts-Hautklinik Kiel, Schittenhelmstr. 7, 24105 Kiel