A Usual Frameshift and Delayed Termination Codon Mutation in Keratin 5 Causes a Novel Type of Epidermolysis Bullosa Simplex with Migratory Circinate Erythema (original) (raw)
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Journal of Investigative Dermatology, 1999
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 E pidermolysis bullosa simplex (EBS) is a group of rare genetic skin disorders with intraepidermal cytolytic blister formation on mechanical trauma . Three major subtypes and various rare types all with autosomal dominant inheritance and additional rarer subtypes have been identified (Gedde-Dahl and . The Weber-Cockayne type of EBS (EBS-WC), with blistering restricted to hands and feet, the Koebner tyoe (EBS-K) with generalized blister formation, and the Dowling-Meara type (EBS-DM) characterized by severe involvement and clumping of the basal keratin network (Anton-Abbreviations: EBS-DM, Dowling-Meara type of epidermolysis bullosa simplex; EBS-K, Koebner type of epidermolysis bullosa simplex; EBS-WC, Weber-Cockayne type of epidermolysis bullosa simplex.
Annals of dermatology, 2014
Epidermolysis bullosa simplex (EBS), an inherited genetic disorder, is most often caused by a dominant-negative mutation in either the keratin 5 (KRT5) or the keratin 14 (KRT14) gene. These keratin mutants result in a weakened cytoskeleton and cause extensive cytolysis. It is important to analyze the KRT5 or KRT14 genes of the patient and their family members by mutational analysis in order to identify genetic defects as well as the need for genetic counseling. In this study, we present a 5-year-old Korean boy who had been developing blisters and erosions on the palms of his hands and soles of his feet since infancy. In addition, while his younger sister and father showed similar clinical manifestation, his mother did not. The patient was diagnosed with EBS based on clinical manifestation, which is characterized by the presence of blisters restricted to the palms and soles, histological findings, and mutational analysis. Mutational analysis of the patient's DNA revealed a thymin...
University of Groningen Epidermolysis bullosa simplex
2010
Chapter 9 fragility, whereas the, for EI characteristic, ichthyotic scaling and neonatal erythroderma were lacking. Of note, the clinical features resembled the phenotype of the patients with the one other, previously reported K1 L12 domain mutation. 8 With transfection studies we have shown that both the novel and the previously reported K1 L12 mutation cause keratin aggregations in vitro. This effect was aggravated upon application of a hypo-osmotic stress stimulus to the cells. In general, the functions of the linker domains of IFs are not well known. The results of the transfection studies performed in chapter 4 indicate that the L12 domain is involved in normal keratin assembly and stress resistance. The K1 L12 domain mutations cause mild phenotypes that might be missed because of the lack of resemblance to classical EI. The observation of unexplainable palmoplantar keratoderma in combination with mild skin fragility, blistering and/or peeling-skin like features should raise the suspicion of EI due to K1 linker domain mutations, especially when suprabasal epidermolysis and/or keratin aggregation is observed in ultrastructural analysis of patient's skin. Notably, in view of this mild blistering phenotype, EI could also be considered as a form of suprabasal EBS, although this was not acknowledged in the latest EB consensus, mainly because EI is generally thought of as an ichthyosiform, scaling disorder. Recently, we have discovered a novel, dominantly inherited missense mutation in the K10 L12 domain in a family with an even milder, more acral-peeling-skin-syndrome-like phenotype (unpublished). In general, mutations in the type II keratin K1 are associated with more severe phenotypes than mutations in K10 (type I). Moreover, recessive loss-of-protein expression mutations have been reported for K10, but not for K1. Similarly, in basal keratins only recessive loss-of-protein mutations have been observed for the type I keratin K14, but not for the type II K5. Furthermore, K5-knockout mice show a more severe and earlier lethal phenotype then the K14-knockout mice. 9 All these findings most likely reflect the functional redundancy of keratins. K14 loss can be (partly) compensated for by another basal keratin, K15, and upregulation of the wound-repair keratin K16. Furthermore, K10 mutations can be (partly) compensated for by expression of an additional type I keratin (K9) in palmoplantar skin. 10 On the other hand, patients with K9 mutations have palmoplantar keratoderma, so apparently K10 cannot compensate for K9 mutations. The type I keratins K5 and K1 have no alternative heterodimer partners, and therefore alterations in these proteins may cause more severe phenotypes. Alternatively, functional properties of type I and type II proteins differ. Of note, the phenomenon of functional redundancy of keratins is interesting in the light of therapeutic options for hereditary keratin disorders, as upregulation of other keratins may reduce the detrimental effect of the mutated keratin. Additional transfection studies will reveal whether the novel K10 L12 domain mutation has the same detrimental effect on the keratin cytoskeleton as the K1 L12 mutations in vitro, or perhaps has no notable effect and therefore causes such a mild phenotype. It would be interesting to perform transfections studies with the both the K1 and K10 linker domain mutations, and with helix boundary motif-affecting mutations as well.
PubMed, 1995
To explore the relationship between abnormal keratin molecules, 10-nm intermediate filament (IF) organization, and epidermal fragility and blistering, we sought to determine the functional consequences of homozygosity for a dominant keratin defect. We describe a family with an autosomal dominant skin-blistering disorder, epidermolysis bullosa simplex, Koebner subtype (EBS-K), that has a novel point mutation, occurring in the keratin 5 gene (KRT5), that predicts the substitution of an evolutionarily conserved lysine by an asparagine residue (K173N). Unlike previous heterozygous mutations located within the initial segment of domain 1A of keratin molecules, K173N heterozygosity did not result in severe disease or clumping of keratin filaments. One family member was found to be homozygous for the K173N allele, having inherited it from each of her affected first-cousin parents. Despite a lack of normal keratin 5 molecules, and an effective doubling of abnormal molecules, available for heterodimerization with keratin 14 during IF formation, there were no significant differences in the clinical severity or the ultrastructural organization of the keratin IF cytoskeleton of the homozygous individual. These data demonstrate that the K173N mutation behaves as a fully dominant allele and indicate that a limited number of abnormal keratin molecules are sufficient to impair cytoskeletal function and elicit epidermal fragility and blistering.
British Journal of Dermatology, 2010
Background Basal epidermolysis bullosa simplex (EBS) is a hereditary skin blistering disorder resulting in most cases from missense mutations in the keratin 5 (KRT5) or keratin 14 (KRT14) genes. Objectives To identify the underlying mutations in different EBS subtypes and correlate genotype and phenotype. Methods Mutation analysis was performed in 53 patients with EBS and their families by direct sequencing of the KRT5 and KRT14 genes. Results We identified 39 different mutations, of which 15 have not been published previously. Three novel deletion ⁄insertion mutations, among them one in-frame duplication, were associated with the rare phenotype of EBS with mottled pigmentation. We identified for the first time a patient with compound heterozygosity for KRT5 mutations causing Dowling-Degos disease and EBS. Conclusions Identification of novel mutations and genotype-phenotype correlations in EBS allow improved understanding of disease pathogenesis as well as better patient management.