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

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.

A novel keratin 12 mutation in a German kindred with Meesmann's corneal dystrophy.

AIM: To study a kindred with Meesmann's corneal dystrophy (MCD) to determine if a mutation within the cornea specific K3 or K12 genes is responsible for the disease phenotype. METHODS: Slit lamp examination of the cornea in four members of the kindred was carried out to confirm the diagnosis of MCD. The region encoding the helix initiation motif (HIM) of the K12 polypeptide was polymerase chain reaction (PCR) amplified from genomic DNA derived from affected individuals in the kindred. PCR products generated were subjected to direct automated sequencing. Restriction enzyme analysis employing Ban I was used to confirm the presence of the mutation in affected individuals of the family. RESULTS: Sequencing of the K12 gene in an affected individual from the family revealed a novel heterozygous missense mutation (413A-->C), predicting the substitution of a proline for a glutamine at codon 130 (Q130P) in the HIM of the K12 protein. The mutation was excluded from 50 normal, unaffected individuals by restriction enyzme analysis and was therefore unlikely to be a common polymorphism. CONCLUSION: A novel missense mutation in the K12 gene leads to MCD in a German kindred. Missense mutations have now been identified within the region encoding the helix initiation motif of the K12 protein in eight of 11 MCD kindreds analysed at the molecular level.

[Progressive disseminated essential telangiectasia with conjunctival involvement]. / Progressive disseminierte essentielle Teleangiektasien mit konjunktivaler Beteiligung.

BACKGROUND: Widespread idiopathic telangiectasia (generalized essential telangiectasia) is a rare skin disorder characterized by the development and gradual spreading of telangiectases. The condition tends to affect women in their midthirties. For no apparent reason telangiectases start to appear to the lower extremities and progress steadily to involve the skin of the trunk, the arms, and the face. General health is not affected by the condition and standard laboratory tests consistently yield normal results. CASE REPORT: In February 1997 a 78-year-old lady was admitted for treatment of cataracta corticonuclearis of her left eye. Complete ophthalmological and dermatological examinations were performed. She presented marked conjunctival telangiectases of both eyes and widespread cutaneous telangiectases involving her face, trunk, arms, and legs. Complete blanching of lesional skin was observed on diascopy. The Rumpel-Leede-test was normal. Cutaneous and conjunctival changes appeared not to be associated with internal disease or bleeding abnormalities. DISCUSSION: The patient presented here shows widespread idiopathic telangiectasia with marked conjunctival involvement. Ocular changes rarely have been reported in patients with generalized essential telangiectasia to date. Concomittant conjunctival and cutaneous telangiectases may be seen in other conditions such as hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease) and ataxia telangiectasia (Louis-Bar syndrome). The former shows an associated bleeding abnormality and is transmitted autosomal dominantly. The latter presents associated neurological signs such as cerebellar ataxia, strabism, nystagmus, apraxia, and mental retardation.

[Mutations in the keratin gene as a cause of Meesman-Wilke corneal dystrophy and autosomal dominant skin cornification disorders]. / Keratin-Gen-Mutationen als Ursache der Epitheldystrophie Meesmann-Wilke und autosomal dominanter Verhornungsstörungen der Haut.

BACKGROUND: Meesmann's corneal dystrophy (OMIM 122,100) is a rare autosomal dominant disorder of the corneal epithelium. It manifests in early childhood and affects both eyes. The disease is characterized by variable patterned dot-like corneal opacities and intraepithelial vesicles, which can be seen by slit-lamp examination and retro-illumination. Further signs include punctate erosions, lacrimation, photophobia, and blepharospasm. Vision is usually only slightly diminished. By histology, the corneal epithelium is irregularly thickened. It shows vacuolated epithelial cells and intraepithelial formation of vesicles. By electron microscopy fibrogranular aggregates are seen in the cytoplasm of epithelial cells. RESULTS: Linkage analyses in descendants of the family described by Meesmann and Wilke and other affected kinships showed that the putative genetic defect locates within the keratin type I gene cluster on chromosome 17 (17q12-21). Molecular genetic analyses in more than ten affected families showed that mutations in the cornea-specific keratin genes K3 and K12 represent the causative genetic defects of the disease phenotype. CONCLUSION: Comparative studies in autosomal dominant skin disorders of cornification suggest that the mutations identified in patients with Meesmann's corneal dystrophy exert dominant negative effects on keratin filament assembly. Disturbed filament formation results in intracellular keratin clumping, identifiable as fibrogranular aggregates. As a result the mechanical resilience of the affected cells and the epithelial tissue appears markedly reduced. Whether abnormalities of functionally related structural proteins, e.g. desmosomal components, could result in a phenotype similar to Meesmann and Wilke's corneal dystrophy remains to be seen.

Molecular genetics of Meesmann's corneal dystrophy: ancestral and novel mutations in keratin 12 (K12) and complete sequence of the human KRT12 gene.

Recently, we identified the first mutations in corneal keratins K3 and K12 in families with Meesmann's corneal dystrophy (MCD). Here, we sequenced all regions of the human K12 gene, to enable mutation detection for all exons using genomic DNA as a template. The human K12 genomic sequence spans 5919 bp and consists of eight exons. A microsatellite dinucleotide repeat was identified within intron 3, which was highly polymorphic and which we developed for use in genotype analysis. In addition, two mutations in the helix initiation motif of K12 were found in families with MCD. A novel mutation was detected in an American kindred, 410T-->C, which predicts the amino acid substitution M129T. In a German family, mutation 428G-->C was identified, predicting amino acid change R135T. The latter mutation was identical to that which we identified in the original kindred described by Meesmann. Using the intragenic microsatellite polymorphism in K12 and additional flanking markers, we were able to show that this family shares a common haplotype with the original Meesmann kindred. These results strongly imply that R135T represents an ancestral mutation in the German population. Both mutations occur in the highly conserved helix initiation motif of the K12 polypeptide. A total of eight mutations have now been reported in the K12 gene.