and/or aims): This proposal is based on the applicants' recent demonstration that two large kindreds with EBS show linkage of disease phenotype to specific loci on chromosomes 12q and 17q, sites of clusters of type II and I keratin genes, respectively. The investigators now propose to identify the mutated genes at these sites, suggesting that keratin mutations underlie the epidermal fragility in these two kindreds. The strategy will be to establish that these two linkage loci do indeed lie close to the genes for epidermal keratins, and to assess the latter genes for mutations. The etiologic role of mutations, if identified, will be proven by introduction of genes carrying the patients' mutations into cultured keratinocytes or by developing transgenic mice that reproduce the human disease. The investigators also plan to survey other kindreds with EBS for keratin gene mutations so as to identify regions critical for normal protein function. Finally, they propose to test the reported efficacy of retinoid therapy and, if confirmed, investigate the mechanisms responsible for the effect.
