Focal activation of a mutant allele defines the role of stem cells in mosaic skin disorders

Stem cells are crucial for the formation and maintenance of tissues and org ans. The role of stem cells in the pathogenesis of mosaic skin disorders re mains unclear. To study the molecular and cellular basis of mosaicism, we e stablished a mouse model for the autosomal-dominant skin blistering disorde r, epidermolytic hyperkeratosis (MIM 113800), which is caused by mutations in either keratin K1 or K10. This genetic model allows activation of a soma tic K10 mutation in epidermal stem cells in a spatially and temporally con- trolled manner using an inducible Cre recombinase, Our results indicate tha t lack of selective pressure against certain mutations in epidermal stem ce lls leads to mosaic phenotypes. This finding has important implications for the development of new strategies for somatic gene therapy of dominant gen odermatoses.