1. ^*Department of Dermatology and Laboratory of Molecular Dermatology, Rambam Medical Center, Haifa, Israel
2. ^†Department of Dermatology and Cutaneous Biology and the Jefferson Institute of Molecular Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA
3. ^‡National Skin Center, Singapore

Correspondence: Eli Sprecher, M.D., Ph.D., Department of Dermatology and Laboratory of Molecular Dermatology, Rambam Medical Center, Haifa, Israel; Email: e_sprecher@rambam.health.gov.il

Received 22 August 2002; Revised 22 October 2002; Accepted 29 October 2002.

Abstract

The cytoskeleton of epithelial cells is formed by heteropolymeric keratin proteins characterized by a central -helical rod flanked by nonhelical head and tail domains of variable sequence. Most mutations described in 18 distinct keratins disrupt highly conserved regions at the boundaries of the rod, which have been recognized as zones of overlap during keratin alignment and assembly into intermediate filaments. We recently reported the first mutation located in a keratin tail domain (V2) in ichthyosis hystrix Curth–Macklin. In this study, we report two novel frameshift mutations that are predicted to alter the tail of keratin 1 or keratin 5, leading to an atypical form of epidermolytic hyperkeratosis and a mild form of epidermolysis bullosa simplex, respectively. Mutation analysis of the patient with epidermolytic hyperkeratosis revealed a de novo heterozygous nucleotide insertion (1752insG) in exon 9 of KRT1, predicted to result in an aberrant 69 residue keratin 1 tail. In the patient with mild epidermolysis bullosa simplex, we identified a single nucleotide deletion (1635delG) in exon 9 of KRT5 leading to frameshift and translation of an abnormal V2 domain, 35 amino acids longer than the native keratin 5 tail. Our results, together with previous observations, establish the existence of a subgroup of keratin disorders due to frameshift mutations altering the keratin tail domains that are characterized by phenotypic heterogeneity.