Keratin gene mutations cause Meesmann's corneal dystrophy and autosomal dominant skin disorders of cornification

Background: Meesmann's corneal dystrophy (OMIM 122100) is a rare autosomal dominant disorder of the corneal epithelium. It manifests in early childhoo d 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 retroillumination. Further signs include punc tate erosions, lacrimation, photophobia, and blepharospasm. Vision is usual ly only slightly diminished. By histology, the corneal epithelium is irregu larly thickened. It shows vacuolated epithelial cells and intraepithelial f ormation of vesicles. By electron microscopy fibrogranular aggregates are s een in the cytoplasm of epithelial cells. Results: Linkage analyses in descendants of the family described by Meesman n and Wilke and other affected kinships showed that the putative genetic de fect 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 th e causative genetic defects of the disease phenotype. Conclusion: Comparative studies in autosomal dominant skin disorders of cor nification suggest that the mutations identified in patients with Meesmann' s corneal dystrophy exert dominant negative effects on keratin filament ass embly. Disturbed filament formation results in intracellular keratin clumpi ng, identifiable as fibrogranular aggregates. As a result the mechanical re silience of the affected cells and the epithelial tissue appears markedly r educed. 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.