Epidermolytic Hyperkeratosis and Epidermolysis Bullosa Simplex Caused by Frameshift Mutations Altering the V2 Tail Domains of Keratin 1 and Keratin 5

Abstract

The cytoskeleton of epithelial cells is formed by heteropolymeric keratin proteins characterized by a central alpha-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.

Defining the Properties of the Nonhelical Tail Domain in Type II Keratin 5: Insight from a Bullous Disease-causing Mutation

“…Even though these C-terminal truncations occur only five residues apart within the highly conserved TYRK 472 LLEGE 477 motif at the very end of the K5 rod domain, electron microscopy showed that only E477 is associated with keratin aggregates typical of DowlingMeara EBS in basal cells. In yet another case involving K5's C terminus, a nucleotide deletion, 1635delG, was found within K5's exon 9 in a sporadic case of Weber-Cockayne (mild) EBS (Sprecher et al, 2003). The resulting frameshift is in-phase with the K5-1649delG mutation, but the properties of this mutant have not been described.…”

“…16, March 2005and disfiguring condition apparent to EHK), striate palmoplantar keratoderma, and mild epidermolytic hyperkeratosis (Sprecher et al, 2001(Sprecher et al, , 2003Whittock et al, 2002). K1 is expressed in the differentiating layers of interfollicular epidermis (O'Guin et al, 1990;Fuchs, 1995).…”

The keratins and their disorders

“…The mechanism by which this particular mutation affects pigmentation is not known but it has been proposed that the V1 domain is involved in interactions with melanosomes [Uttam et al, 1996]. A mutation has also been described that affects the V2 domain of K5 and results in a very mild form of EBS-WC [Sprecher et al, 2003].…”

Striate Palmoplantar Keratoderma Showing Transgrediens in a Patient Harbouring Heterozygous Nonsense Mutations in Both DSG1 and SERPINB7

“…1F). Clinically, we initially suspected KRT1 mutation-induced SPPK with a V2 frameshift, which has been reported to cause SPPK (9). Histologically, it was necessary to consider a DSG1 mutation, as there have been reports of this mutation leading to acantholysis (10).…”