DISRUPTION OF HUMAN LIMB MORPHOGENESIS BY A DOMINANT-NEGATIVE MUTATION IN CDMP1

Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder c haracterized by severe limb shortening and dysmorphogenesis. We have i dentified a causative point mutation in the gene encoding the bone mor phogenetic protein (BMP)-like molecule, cartilage-derived morphogeneti c protein-1 (CDMP-1). The mutation substitutes a tyrosine for the firs t of seven highly conserved cysteine residues in the mature active dom ain of the protein, We demonstrate that the mutation results in a prot ein that is not secreted and is inactive in vitro. It produces a domin ant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the fo rmation of heterodimers. The mutation and its proposed mechanism of ac tion provide the first human genetic indication that composite express ion patterns of different BMPs dictate limb and digit morphogenesis.