The autosomal dominant epidermolysis bullosa simplex (EBS) results from mutations of keratin 5 (K5) or keratin 14 (K14), a cytoskeletal protein expressed in the basal keratinocytes of the epidermis. To date, a number of mutations of K5/14 have been demonstrated in EBS. In the present study, we collected 15 pedigrees with EBS from Japan and Poland, including clinically three major subtypes ; Weber-Cockayne, Köbner, and Dowling-Meara, as well as two cases of EBS with mottled pigmentation. Then we isolated genomic DNA and sequenced
KRT5 and
KRT14 to add to the mutation database. We identified ten different heterozygous missense mutations in 13 pedigrees : P25L, A180E, L325P, R331D, G476D, E477G, and E477K in K5 ; M119L, V133 A and V133M in K14, none of which were found in 100 control chromosomes. Mutations associated with Dowling-Meara (pedigrees 9-12) resided in the highly conserved 20 amino acids at the ends of the 1A or 2B domains in K5/14. Direct nucleotide sequencing of two cases of EBS with mottled pigmentation (pedigrees 14 and 15) revealed a heterozygous P25L mutation in K5. However, no genotype-phenotype correlation was identified in pedigrees with Weber-Cockayne or Köbner. Further molecular analysis of K5/14 will be necessary to extend genotype-phenotype correlation and to provide accurate diagnosis and genetic informed consent to families with EBS.
View full abstract