A mutation (met→arg) in the type I keratin (K14) gene responsible for autosomal dominant epidermolysis bullosa simplex

Humphries, Marian M.; Sheils, Denise M.; Farrar, G. Jane; Kumar‐Singh, Rajendra; Kenna, Paul F.; Mansergh, Fiona C.; Jordan, Siobhán A.; Young, Melodie; Humphries, Peter

doi:10.1002/humu.1380020107

Cited by 61 publications

(25 citation statements)

References 38 publications

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“…The highly conserved boundary motifs of the cen tral rod domain appear to be essential for correct fila ment assembly Fuchs 1987, 1989; Hatzfeld and Weber I99I; Letai et al 1992), and missense muta tions in these regions result in filament aggregation and the most severe dominant skin fragility syndromes such as Dowling-Meara EBS Stephens et al 1993). Mutations occurring be tween these conserved end domains, including a codon deletion, appear to result in milder phenotypes (Chan et al 1993;Chen et al 1993;Humphries et al 1993;Rugg et al 1993a). Here, we describe ablation of Kl4 producing a severe clinical phenotype.…”

Section: Discussionmentioning

confidence: 99%

A functional "knockout" of human keratin 14.

Rugg¹,

McLean²,

Lane³

et al. 1994

Genes Dev.

166

124

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Section: Discussionmentioning

confidence: 99%

A functional "knockout" of human keratin 14.

Rugg¹,

McLean²,

Lane³

et al. 1994

Genes Dev.

166

124

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“…In all prior genetic studies of severe EBS, heterozygous point mutations or small deletions were found in the coding sequences of K14 or K5 alleles (Bonifas et al 1991;Coulombe et al 1991b;Lane et al 1992;Chen et al 1993;Dong et al 1993;Humphries et al 1993;Stephens et al 1993). Typ ically, a patient with a severe case of EBS, as the first occurrence of the disease in a family, will have a spon taneous heterozygous K5 or K14 mutation at a codon especially critical for 10-nm filament assembly.…”

Section: A Premature Termination Codon In Both Alleles Of K14mentioning

confidence: 99%

A human keratin 14 "knockout": the absence of K14 leads to severe epidermolysis bullosa simplex and a function for an intermediate filament protein.

Chan¹,

Anton‐Lamprecht²,

Yu³

et al. 1994

Genes Dev.

184

128

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Since their discovery, the hinction of intermediate filaments (IFs) has remained obscure. In skin, epidermal cells have extensive cytoskeletal architectures of IFs, composed of type I and type II keratin heterodimers. Clues to possible functions of these proteins have come from recent studies showing that several autosomal-dominant, blistering skin disorders are caused by defects in genes that encode epidermal keratins. These diseases all exhibit cell degeneration and keratin network perturbations in cells that express the particular mutant keratin gene. However, it is not clear from these studies whether cytolysis arises from the presence of large insoluble keratin aggregates that compromise cellular physiology or from the absence of an extensive keratin filament network, which jeopardizes mechanical integrity. We report here the analysis of an extremely rare case of severe recessive epidermolysis bullosa simplex (EBS), where the patient lacks a discernible keratin filament network in basal epidermal cells. Genetic analyses revealed a homozygous point mutation that yielded a premature termination codon in the major basal type I keratin gene and caused complete ablation of K14. The consanguineous parents were normal, each harboring one copy of the null K14 mutation. Analysis of cultured keratinocytes enabled us to document that the loss of K14 is not compensated for by the up-regulation of any other type I keratin. When taken together with the in vivo studies showing the presence of cell fragility generated from the lack of an extensive basal keratin network, these findings provide the first clear demonstration of loss of function associated with the absence of an IF protein in vivo.[Key Words: Intermediate filaments; epidermal keratin; epidermolysis bullosa simplex; epidermolytic hyperkeratosis]

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Wagner

Hintner

Bauer

et al. 2011

Experimental Dermatology

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An intact keratin 5 ⁄ keratin 14 intermediate filament cytoskeleton is vital for the integrity of basal keratinocytes and for the development and maintenance of epidermal structures. In patients with epidermolysis bullosa simplex Dowling-Meara (EBS-DM), heterozygous mutations in the keratin 14 gene in keratinocytes cause a cytoskeletal collapse leading to fragile cells susceptible to cellular stress. The primary aim of this work was to extend analysis of differentially expressed genes in an EBS-DM model cell line to obtain insights into the molecular consequences resulting from the keratin 14 mutation. In a first step, suppression subtractive hybridization (SSH), a powerful technology to enrich for differentially expressed genes, was used to identify genes whose up-regulation may be a direct or indirect result of the keratin 14 mutation, R125P. We discovered 55 candidate genes (SSH genes) that were further analysed by RTq-PCR. Of the 55 SSH genes, 14 (25.45%) were found to be congruently up-regulated. Bioinformatic analysis revealed significant enrichment of genes regulating epidermal development, migration, apoptosis and wound healing.

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A mutation (met→arg) in the type I keratin (K14) gene responsible for autosomal dominant epidermolysis bullosa simplex

Cited by 61 publications

References 38 publications

A functional "knockout" of human keratin 14.

A functional "knockout" of human keratin 14.

A human keratin 14 "knockout": the absence of K14 leads to severe epidermolysis bullosa simplex and a function for an intermediate filament protein.

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

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