title: The mutational spectrum of brachydactyly type C.
abstract: Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D019556:COS Cells; D005260:Female; D016368:Frameshift Mutation; D015870:Gene Expression; D055428:Growth Differentiation Factor 5; D006228:Hand Deformities, Congenital / Q000145:classification / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype
chemical_list: D019485:Bone Morphogenetic Proteins; C525893:GDF5 protein, human; D055428:Growth Differentiation Factor 5