MUTATIONS IN THE H1 AND 1A DOMAINS IN THE KERATIN-1 GENE IN EPIDERMOLYTIC HYPERKERATOSIS

In the autosomal dominant disorder epidermolytic hyperkeratosis, the s tructural integrity of the keratin intermediate filaments is altered i n the suprabasal layers of the epidermis. We and others have used gene tic linkage studies and mutation analysis to establish that single ami no acid substitutions in either the keratin 1 or keratin 10 chains can cause epidermolytic hyperkeratosis. However, a larger database of mut ations is required to better understand the relationship between speci fic mutations in these keratin chains and their effect on keratin fila ment structure. A larger database will also provide a catalog that may be useful for genetic counseling purposes. In this paper, we report t he identification of three new mutations of the keratin 1 chain of epi dermolytic hyperkeratosis probands in highly conserved residues in the H1 or beginning of the 1A rod domain segments. These correspond to re gions involved in molecular overlaps between neighboring molecules in keratin filaments. Using an in vitro assay, synthetic peptides bearing these substitutions show diminished capacity to disassemble preformed filaments in vitro in comparison to the wild type peptides. Moreover, analyses of all mutations in epidermolytic hyperkeratosis known to da te demonstrate remarkable clustering in the molecular overlap region. We conclude that non-conservative substitutions in the overlap region are likely to interfere with normal keratin filament structure and fun ction, leading to pathology.