Abstract
Epidermolysis bullosa simplex (EBS) is a hereditary genodermatosis characterised by trauma-induced intraepidermal blistering of the skin. EBS is mostly caused by mutations in the KRT5 and KRT14 genes. Disease severity partially depends on the affected keratin type and may be modulated by mutation type and location. The aim of our study was to identify the molecular defects in KRT5 and KRT14 in a cohort of 46 Polish and one Belarusian probands with clinical suspicion of EBS and to determine the genotype–phenotype correlation. The group of 47 patients with clinical recognition of EBS was enrolled in the study. We analysed all coding exons of KRT5 and KRT14 using Sanger sequencing. The pathogenic status of novel variants was evaluated using bioinformatical tools, control group analysis (DNA from 100 healthy population-matched subjects) and probands’ parents testing. We identified mutations in 80 % of patients and found 29 different mutations, 11 of which were novel and six were found in more than one family. All novel mutations were ascertained as pathogenic. In the majority of cases, the most severe genotype was associated with mutations in highly conserved regions. In some cases, different inheritance mode and clinical significance, than previously reported by others, was observed. We report 11 novel variants and show novel genotype–phenotype correlations. Our data give further insight into the natural history of EBS molecular pathology, epidemiology and mutation origin.
Highlights
Epidermolysis bullosa simplex (EBS) is a rare hereditary genodermatosis characterised by intraepidermal blistering of the skin upon mild trauma (Fine 2010)
Epidermolysis bullosa simplex (EBS) is a hereditary genodermatosis characterised by trauma-induced intraepidermal blistering of the skin
In more than 75 % of cases, EBS is caused by mutations in the KRT5 and KRT14 genes, affecting keratin 5 (K5) or keratin 14 (K14), respectively (Bolling et al 2011); mutations in nine other genes were reported to cause the EBS phenotype (Fine et al 2014)
Summary
Epidermolysis bullosa simplex (EBS) is a rare hereditary genodermatosis characterised by intraepidermal blistering of the skin upon mild trauma (Fine 2010). Regardless of the keratin type affected, most of these mutations change amino acid residues in the central L-helical rod domain, leading to more severe EBS phenotypes. Milder EBS is often caused by mutations in the K5 located in non-helical linker regions and in the head domain (Coulombe and Lee 2012). The severity of the disease is further modulated by the location of substituted amino acid within repetitive motif [i.e. heptad structure (abcdefg)n] of the helical domain. According to the superhelix model, the phenotype caused by substitutions of amino acids directly involved in the interaction between heterodimeric keratins is more severe compared to those affecting other residues (Pauling and Corey 1953; Müller et al 2006). Other data indicate that mutation dosage and biophysical properties of introduced amino acids are of importance with regards to exacerbation of the EBS severity (Shinkuma et al 2013; Ołdak et al 2011)
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