Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients.

[epidermolysis bullosa simplex]

Epidermolysis bullosa simplex (EBS ) is a mechanobullous genodermatosis that may be caused by mutations in the genes KRT 5 and KRT 14 encoding the basal epidermal keratins 5 (K 5 ) and 14 (K 14 ). Three main clinical subtypes of EBS exist , differing in onset , distribution and severity of skin blistering . Previous reports of KRT 5 and KRT 14 mutations suggest a correlation between the location of the mutation and the severity of the associated EBS phenotype .The prevalence of KRT 5 /KRT 14 mutations and the genotype-phenotype correlation in the largest tissue-confirmed EBS population is investigated .K RT 5 and KRT 14 genomic DNA and cDNA sequences of 76 clinically well-defined unrelated EBS probands were amplified and then subjected to direct sequencing and product length analysis . Immunofluorescence microscopy on patients ' skin biopsies with antibodies against K 5 and K 14 was performed to study protein expression .In 57 of 76 (75 %) probands 41 different KRT 5 and KRT 14 mutations were identified , of which 12 were novel . Mutations affecting the highly conserved helix boundary motifs of the rod domains of K 5 and K 14 , and the K 14 helix initiation motif in particular , were associated with the severest , EBS Dowling-Meara , phenotype . In 21 EBS probands (37 %) the mutation was de novo . In 19 probands (25 %) KRT 5 or KRT 14 mutations were excluded .The phenotype-genotype correlation observed in this large EBS population underscores the importance of helix boundary motifs for keratin assembly . Only three -quarters of biopsy-confirmed EBS probands have KRT 5 or KRT 14 mutations , indicating genetic heterogeneity in EBS . Alternative gene candidates are discussed .