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

P>BackgroundEpidermolysis bullosa simplex (EBS) is a mechanobullous genodermatosis that may be caused by mutations in the genes KRT5 and KRT14 encoding the basal epidermal keratins 5 (K5) and 14 (K14). Three main clinical subtypes of EBS exist, differing in onset, distribution and severity of skin blistering. Previous reports of KRT5 and KRT14 mutations suggest a correlation between the location of the mutation and the severity of the associated EBS phenotype.ObjectivesThe prevalence of KRT5/KRT14 mutations and the genotype-phenotype correlation in the largest tissue-confirmed EBS population is investigated.MethodsKRT5 and KRT14 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 K5 and K14 was performed to study protein expression.ResultsIn 57 of 76 (75%) probands 41 different KRT5 and KRT14 mutations were identified, of which 12 were novel. Mutations affecting the highly conserved helix boundary motifs of the rod domains of K5 and K14, and the K14 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%) KRT5 or KRT14 mutations were excluded.ConclusionsThe 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 KRT5 or KRT14 mutations, indicating genetic heterogeneity in EBS. Alternative gene candidates are discussed.