Preaxial polydactyly: a model for defective long-range regulation in congenital abnormalities

Point mutations in the long-range, limb-specific regulatory element of the SHH gene are responsible for the human limb abnormality called preaxial polydactyly (PPD). Disruptions of regulatory elements in developmental genes are a small but increasingly significant class of mutations responsible for congenital defects. Identifying regulatory elements that might reside hundreds of kilobases from their relevant genes is difficult but rendered possible by the emerging field of comparative genomics. Genetic analysis of PPD highlights the notion that regulatory mutations might generate phenotypes distinct from any of those identified for coding region mutations.