GENOMIC ORGANIZATION AND FINE MAPPING OF THE KERATIN 2E GENE (KRT2E) - K2E V1 DOMAIN POLYMORPHISM AND NOVEL MUTATIONS IN ICHTHYOSIS BULLOSAOF SIEMENS

We and others have previously shown that ichthyosis bullosa of Siemens , an autosomal dominant disorder characterized by epidermal thickening and blistering, is caused by mutations in the late-differentiation ke ratin K2e, Here, we have determined the genomic organization and compl ete sequence of the KRT2E gene, which consists of nine exons, spanning 7634 bp of DNA, The gene was mapped by high-resolution radiation-hybr id mapping to the interval between microsatellite markers D12S368 and CHLC.GATA11B02.11112. Several intragenic polymorphisms were detected, including an 18 bp duplication in exon 1, corresponding to the V1 doma in of the K2e polypeptide. Genomic polymerase chain reaction condition s were optimized for all exons, and two novel mutations, N192Y in the 1A domain and E482K in the 2B domain of K2e, were found in ichthyosis bullosa of Siemens families. Mutations were excluded from 50 normal un related individuals by restriction analysis. These results emphasize t hat mutations in K2e underlie ichthyosis bullosa of Siemens and provid e a comprehensive mutation detection strategy for ongoing studies of k eratinizing disorders.