Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice

Analysis of classical mouse mutations has been useful in the identification and study of many genes. We previously mapped Sox18, encoding an SRY-relat ed transcription factor(1), to distal mouse chromosome 2 (ref, 2), This reg ion contains a known mouse mutation, ragged (Ra), that affects the coat and vasculature(3-5). Here we have directly evaluated Sox18 as a candidate for Ra, We found that Sox18 is expressed in the developing vascular endotheliu m and hair follicles in mouse embryos. Furthermore, we found no recombinati on between Sox18 and Ra in an interspecific backcross segregating for the R a phenotype, We found point mutations in Sox18 in two different Ra alleles that result in missense translation and premature truncation of the encoded protein. Fusion proteins containing these mutations lack the ability to ac tivate transcription relative to wild-type controls in an in vitro assay. O ur observations implicate mutations in Sox18 as the underlying cause of the Ra phenotype, and identify Sox18 as a critical gene for cardiovascular and hair follicle formation.