Fraser syndrome is a rare recessive disorder characterized by cryptophthalmos, syndactyly, renal defects, and a range of other developmental abnormalities. Because of their extensive phenotypic overlap, the mouse blebbing mutants have been considered models of this disorder, and the recent isolation of mutations inFras1in both theblebbedmouse and human Fraser patients confirms this hypothesis. Here we report the identification of mutations in an extracellular matrix geneFras1-related extracellular matrix gene 1(Frem1) in both the classichead blebsmutant and in anN-ethyl-N-nitrosourea-induced allele. We show that inactivation of the gene results in the formation ofin uteroepidermal blisters beneath the lamina densa of the basement membrane and also in renal agenesis.Frem1is expressed widely in the developing embryo in regions of epithelial/mesenchymal interaction and epidermal remodeling. Furthermore,Frem1appears to act as a dermal mediator of basement membrane adhesion, apparently independently of the other known “blebs” proteins Fras1 and Grip1. Unlike bothFras1andGrip1mutants, collagen VI and Fras1 deposition in the basement membrane is normal, indicating that the protein plays an independent role in epidermal differentiation and is required for epidermal adhesion during embryonic development.