Molecular Genetics of Inherited Disorders of Epidermal Keratins

Abstract

Keratins are a major constituent of the epidermal cell cytoskeleton. Apart from their contribution to cell ability to resist mechanical stress, they have been shown to regulate additional biological processes of importance such as protein synthesis, cell migration and apoptosis. Much of this knowledge has been gained through the study of rare disorders, known as keratinopathies, which are caused by mutations in genes encoding the various epidermal keratins . Recently, novel therapeutic approaches for keratin disorders have been tested successfully, thus raising new hopes for the treatment of this group of inherited skin diseases. Key concepts Keratins are major constituent of epithelial cell cytoskeleton and confer to the cell the ability to resist mechanical stress. Keratins play additional nonstructural role such regulation of cell growth, protein synthesis, cell migration and apoptosis. Keratin disorders manifest with clinical and pathological features that reflect the site of expression of the mutant keratins and the specific function of the keratin domain affected by the causative mutation. Keratin disorders are characterized by genetic heterogeneity, namely a single clinical phenotype can result from mutations in different (but sometimes functionally related) genes (e.g. epidermolysis bullosa caused by mutations in at least five genes). Keratin disorders are characterized by phenotypic heterogeneity, namely mutations in the very same gene can give rise to multiple distinct phenotypes (e.g. mutations in KRT1 can cause at least four distinct diseases). Keratin mutations exert a dominant negative effect; hence current approaches are aimed at eliminating the mutant proteins from the skin. Based on this concept, a first clinical trial in humans has recently been launched to test the effect of a siRNA to treat pachyonychia congenita.