We studied a kindred with recessive epidermolysis bullosa simplex in which the affected members lacked expression of the basal cell keratin 14. The patients had severe generalized skin blistering that improved slightly with age. The basal cells of the patients did not express keratin 14 and contained no keratin intermediate filaments. The expression of keratin 5, the obligate copolymer of keratin 14, was slightly reduced. The expression of keratin 15, the alternative basal cell keratin, was increased, suggesting upregulation or stabilization to compensate for the lack of keratin 14. The expression of keratin 16, keratin 17, and keratin 19 in the patient's skin was not different from controls. Immunoelectron microscopy showed a loose network of keratin 5/keratin 15 protofilaments in the basal cells. Keratin 15 filaments did not aggregate into higher order bundles. Sequence analysis of genomic DNA revealed a homozygous mutation in the 3'-acceptor splice site of intron 1 (1840 A-->C) in the affected individuals. This mutation led to the skipping of exon 2 in 24% of the KRT14 transcripts and to the use of a cryptic splice site in 76% of the transcripts. Premature termination codons were generated in all transcripts (codons 175+1 or 175+29), leading to a truncated keratin 14 protein within the helical 1B rod domain. The disorder was associated with circumscribed hyperkeratotic lesions with the histology of epidermolytic hyperkeratosis. The prognosis of keratin 14 ablation is much better in the human than in the mouse.

The frequency of the type of mutations in the RB1 gene in our unbiased national cohort is the same as the mutation spectrum described worldwide. Furthermore, our RB1 mutation detection regimen achieves a high scanning sensitivity.

No abstract

No abstract