Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK

Craniometaphyseal dysplasia (CMD) is a rare skeletal disorder characterized by progressive thickening and increased mineral density of craniofacial bo nes and abnormally developed metaphyses in long bones. Linkage studies mapp ed the locus for the autosomal dominant form of CMD to an similar to5-cM in terval on chromosome 5p, which is defined by recombinations between loci D5 S810 and D5S1954. Mutational analysis of positional candidate genes was per formed, and we describe herein three different mutations, in five different families and in isolated cases, in ANK, a multipass transmembrane protein involved in the transport of intracellular pyrophosphate into extracellular matrix. The mutations are two in-frame deletions and one in-frame insertio n caused by a splicing defect. All mutations cluster within seven amino aci ds in one of the six possible cytosolic domains of ANK. These results sugge st that the mutated protein has a dominant negative effect on the function of ANK, since reduced levels of pyrophosphate in bone matrix are known to i ncrease mineralization.