Identification of Novel and Known Mutations in the Genes for Keratin 5 and 14 in Danish Patients with Epidermolysis Bullosa Simplex: Correlation Between Genotype and Phenotype

Abstract

Epidermolysis bullosa simplex (EBS) is a group of autosomal dominant inherited skin diseases caused by mutations in either the keratin 5 (K5) or the keratin 14 (K14) genes and characterized by development of intraepidermal skin blisters. The three major subtypes of EBS are Weber-Cockayne, Koebner, and Dowling-Meara, of which the Dowling-Meara form is the most severe. We have investigated five large Danish families with EBS and two sporadic patients with the Dowling-Meara form of EBS. In the sporadic Dowling-Meara EBS patients, a novel K14 mutation (N123S) and a previously published K5 mutation (N176S) were identified, respectively. A novel K14 mutation (K116N) was found in three seemingly unrelated families, whereas another family harbored a different novel K14 mutation (L143P). The last family harbored a novel K5 mutation (L325P). The identified mutations were not present in more than 100 normal chromosomes. Six polymorphisms were identified in the K14 gene and their frequencies were determined in normal controls. These polymorphisms were used to show that the K14 K116N mutation was located in chromosomes with the same haplotype in all three families, suggesting a common ancestor. We observed a strict genotype-phenotype correlation in the investigated patients as the same mutation always resulted in a similar phenotype in all individuals with the mutation, but our results also show that it is not possible to predict the EBS phenotype merely by the location (i.e., head, rod, or linker domains) of a mutation. The nature of the amino acid substitution must also be taken into account.

Novel and recurrent mutations in keratinKRT5andKRT14genes in epidermolysis bullosa simplex: implications for disease phenotype and keratin filament assembly

“…This notion is supported by a multitude of EBS-DM mutations affecting the respective amino acid residues (Cassidy et al, 2002) as well as by the novel mutation K14-p.Asn123Lys that corresponds to position e of the heptad. Another mutation K14-p.Asn123Ser involving the same residue has been found in a previously analysed EBS-DM case (Sorensen et al, 1999).In contrast to a reported Japanese EBS-K patient with mutation K14-p. Leu122Phe (Yamanishi et al, 1994) our two sporadic patients carrying the same mutation both presented typical features of EBS-DM and involvement of the oral mucosa. Furthermore, pathognomonic KIF clumping was demonstrated by EM in one case.…”

Epidermolysis Bullosa Simplex in Israel

“…E167K and V324D affect regions previously shown to be mutated in WeberCockayne cases of EBS. [11][12][13] L311P occurred in the 1B domain, at a highly unusual site for mutations in EBS. 4 This region is considered less critical for normal KRT5 function during KIF assembly.…”

Gene expression analysis of an epidermolysis bullosa simplex Dowling‐Meara cell line by subtractive hybridization: recapitulation of cellular differentiation, migration and wound healing

“…Phenotypes in EBS are primarily the consequence of mutations in type 2 keratin 5 (K5) or type 1 keratin 14 (K14) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Co-expression of K5 and K14 is a hallmark of highly mitotic basal layer epidermal keratinocytes (12)(13)(14)(15).…”