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Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy
A D Irvine1, L D Corden, O Swensson
1Department of Dermatology, Belfast City Hospital, UK.
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.
Insights
Genetic mutations in cornea-specific keratins K3 and K12 cause Meesmann
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- Meesmann's corneal dystrophy (MCD) is an inherited condition causing corneal fragility.
- The corneal epithelium's cytoskeleton relies on specific keratins, K3 and K12.
- The genetic cause of MCD was previously unknown.
Purpose of the Study:
- To investigate the molecular basis of Meesmann's corneal dystrophy.
- To identify specific mutations in keratin genes K3 and K12 associated with MCD.
Main Methods:
- Gene mapping using radiation hybrids to locate keratin genes.
- Linkage analysis in affected families to associate genetic loci with the phenotype.
- DNA sequencing to identify mutations in K3 and K12 genes.
Main Results:
- Linkage was established between MCD and the K12 locus in a German family.
- The phenotype segregated with K3 or K12 loci in Northern Irish families.
- Heterozygous missense mutations (K3 E509K, K12 V143L, K12 R135T) were identified and co-segregated with MCD, absent in controls.
Conclusions:
- Dominant-negative mutations in cornea-specific keratins K3 and K12 are the molecular cause of Meesmann's corneal dystrophy.
- These mutations occur in critical keratin helix boundary motifs, disrupting cytoskeletal function and leading to corneal fragility.