Mutations in @entity4205 and @entity6881 cause epidermolysis bullosa simplex in 75% of the XXXX .

@entity1 @entity6881 @entity4205 @entity8612
BACKGROUND: @entity8612 ( @entity8612 ) is a mechanobullous genodermatosis that may be caused by mutations in the genes @entity4205 and @entity6881 encoding the basal epidermal keratins 5 (K5) and 14 ( @entity6881 ). Three main clinical subtypes of @entity8612 exist, differing in onset, distribution and severity of skin blistering. Previous reports of @entity4205 and @entity6881 mutations suggest a correlation between the location of the mutation and the severity of the associated @entity8612 phenotype. OBJECTIVES: The prevalence of @entity4205 / @entity6881 mutations and the genotype-phenotype correlation in the largest tissue-confirmed @entity8612 population is investigated. METHODS: @entity4205 and @entity6881 genomic DNA and cDNA sequences of 76 clinically well-defined unrelated @entity8612 probands were amplified and then subjected to direct sequencing and product length analysis. Immunofluorescence microscopy on @entity1 ' skin biopsies with antibodies against K5 and @entity6881 was performed to study protein expression. RESULTS: In 57 of 76 (75%) probands 41 different @entity4205 and @entity6881 mutations were identified, of which 12 were novel. Mutations affecting the highly conserved helix boundary motifs of the rod domains of K5 and @entity6881 , and the @entity6881 helix initiation motif in particular, were associated with the severest, @entity8612 Dowling-Meara, phenotype. In 21 @entity8612 probands (37%) the mutation was de novo. In 19 probands (25%) @entity4205 or @entity6881 mutations were excluded. CONCLUSIONS: The phenotype-genotype correlation observed in this large @entity8612 population underscores the importance of helix boundary motifs for keratin assembly. Only three-quarters of biopsy-confirmed @entity8612 probands have @entity4205 or @entity6881 mutations, indicating genetic heterogeneity in @entity8612 . Alternative gene candidates are discussed.
