Campomelic dysplasia (CD) is an autosomal dominant, perinatal lethal skeletaldysplasia characterized by a small chest and short long bones with bowing of thelower extremities. CD is the result of heterozygosity for mutations in the geneencoding the chondrogenesis master regulator, SOX9. Loss‐of‐function mutationshave been identified in most CD cases so it has been assumed that the disease resultsfrom haploinsufficiency for SOX9. Here, we identified distal truncating SOX9mutations in four unrelated CD cases. The mutations all leave the dimerization andDNA‐binding domains intact and cultured chondrocytes from three of the four casessynthesized truncated SOX9. Relative to CD resulting from haploinsufficiency, therewas decreased transactivation activity toward a major transcriptional target, COL2A1,consistent with the mutations exerting a dominant‐negative effect. For one of thecases, the phenotypic consequence was a very severe form of CD, with a pronouncedeffect on vertebral and limb development. The data identify a novel molecularmechanism of disease in CD in which the truncated protein leads to a distinct andmore significant effect on SOX9 function.
