Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy

Abstract

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 epithelium, where K3 and K12 are specifically expressed. We postulated that dominant-negative mutations in these keratins might be the cause of MCD. K3 was mapped to the type-II keratin gene cluster on 12q; and K12 to the type-I keratin cluster on 17q using radiation hybrids. We obtained linkage to the K12 locus in Meesmann's original German kindred (Zmax = 7.53; theta = 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.

Conditional Deletion of the Mouse Klf4 Gene Results in Corneal Epithelial Fragility, Stromal Edema, and Loss of Conjunctival Goblet Cells

“…Mutations in cornea-specific keratin-3 or keratin-12 gene are associated with fragility of the corneal epithelium, a feature of Meesmann's corneal dystrophy observed in the Klf4CN mice ( Fig. 2 and 3) (33,35,49). We have shown that keratin-12 gene expression is downregulated in the Klf4CN corneas and that KLF4 binds and activates the keratin-12 gene promoter (Fig.…”

Phenotypic variability in Meesmann's dystrophy: clinical review of the literature and presentation of a family genetically identical to the original family

“…Meesmann's dystrophy, accordingly, is ascribed to mutations in either the cytokeratin 12 gene or cytokeratin 3 (Irvine et al 1997). These mutations may cause fragility of the corneal epithelium where the two cytokeratins are tissuespecifically expressed.…”

“…These mutations may cause fragility of the corneal epithelium where the two cytokeratins are tissuespecifically expressed. DNA sequence analysis in the Danish family revealed the missense mutation, 428G-> C in the cytokeratin 12 gene that is known (Irvine et al 1997) to cause Meesmann's dystrophy in the large family originating from Germany, described by Behnke & Thiel (1965).…”

High-Resolution Transcript Map of the Region Spanning D12S1629 and D12S312 at Chromosome 12q13: Triple A Syndrome-Linked Region

“…Among the genes placed in the contig, ALK1 was shown to be responsible for hereditary hemorrhagic telangiectasia type 2 (Johnson et al 1996), AMHR2 for persistent Mullerian duct syndrome, type II (Imbeaud et al 1995), and keratin type II genes for various genetic diseases. These keratin-associated diseases include ichthyosis bullosa of Siemens (Rothnagel et al 1994), monilethrix (Healy et al 1995;Winter et al 1997), epidermolysis bullosa simplex (Lane et al 1992), epidermolytic hyperkeratosis (Letai et al 1993), Meesmann corneal dystrophy (Irvine et al 1997), pachyonychia congenita, Jadassohn-Lewandowsky type (Bowden et al 1995), palmoplantar keratoderma, Bothnia type (Lind et al 1994;Kelsell et al 1995), white sponge nevus (Rugg et al 1995). Among these disorders, the genes for all but one, palmoplantar keratoderma, Bothnia type, were identified.…”