A novel three-nucleotide deletion in the helix 2B region of keratin 14 in epidermolysis bullosa simples: δE375

Ma, Chao; Bonifas, JM; Matsumura, Kunie; Blumenfeld, Anat; Epstein, Ernst

doi:10.1093/hmg/2.11.1971

Cited by 57 publications

(27 citation statements)

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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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“…All the previously reported mutations have been within the helix initiation or the helix termination peptide of K5 or K14, mutations in K5 being less frequently reported than K14 mutations (Figure 4b). In other forms of EBS, two previous keratin non-missense mutations have been described: a three-nucleotide deletion (∆E375K14) was reported in EBS-WC, 24 and a mutation of the acceptor splice site of intron 1 in keratin 14 leading to a premature termination codon and absence of protein expression in a kindred with severe recessive EBS. 45 Other splice-site mutations in keratin genes associated with diseases have not been reported to our knowledge.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

“…10,11 Mutations in EBS-K are more internal to the α-helical rod domain, 5,[17][18][19][20] whereas mutations in EBS-WC have been found in the non-helical linker (L1-2) region of K5 and K14, and in the H1 head domain of K5. 12,[21][22][23][24][25][26] Recently, a missense mutation in the non-helical V1 head domain of K5 was identified in patients with EBS with mottled pigmentation. 27,28 We investigated a multigenerational family dominantly affected with EBS-DM for mutations in K5 cDNA.…”

Section: Introductionmentioning

confidence: 99%

Donor splice site mutation in keratin 5 causes in-frame removal of 22 amino acids of H1 and 1A rod domains in Dowling-Meara epidermolysis bullosa simplex

Rugg

Rochat

et al. 1999

Eur J Hum Genet

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Epidermolysis bullosa simplex (EBS) arises from mutations within the keratin 5 and 14 (K5 and K14) genes which alter the integrity of basal keratinocytes cytoskeleton. The majority of these defects are missense mutations in the rod domain, whose locations influence the disease severity. We investigated a large family dominantly affected with the Dowling-Meara form of EBS (EBS-DM). Sequencing of amplified and cloned K5 cDNA from cultured keratinocytes revealed a 66 nucleotide deletion in one allele corresponding to the last 22 amino acid residues encoded by exon 1 (Val164 to Lys185). Sequencing of amplified genomic DNA spanning the mutant region revealed a heterozygous G-to-A transition at + 1 position of the consensus GT donor splice site of intron 1 of K5. This mutation leads to the use of an exonic GT cryptic donor splice site, located 66 nucleotides upstream from the normal donor splice site of intron 1. The corresponding peptide deletion includes the last five amino acids of the H1 head domain and the first 17 amino acids of the conserved amino terminal end of the 1A rod domain, including the first two heptad repeats and the helix initiation peptide. The shortened polypeptide is expressed in cultured keratinocytes at levels which are comparable to the normal K5 protein. This is the first splice site mutation to be reported as a cause of EBS-DM. Owing to the functional importance of the removed region, our data strongly suggest that shortened keratin polypeptide can impair keratin filament assembly in a dominant manner and causes EBS-DM.

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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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A novel three-nucleotide deletion in the helix 2B region of keratin 14 in epidermolysis bullosa simples: δE375

Cited by 57 publications

References 0 publications

A functional "knockout" of human keratin 14.

A functional "knockout" of human keratin 14.

Donor splice site mutation in keratin 5 causes in-frame removal of 22 amino acids of H1 and 1A rod domains in Dowling-Meara epidermolysis bullosa simplex

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

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