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 bones and abnormally developed metaphyses in long bones. Linkage studies mapped the locus for the autosomal dominant form of CMD to an similar to5-cM interval on chromosome 5p, which is defined by recombinations between loci D5S810 and D5S1954. Mutational analysis of positional candidate genes was performed, 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 insertion caused by a splicing defect. All mutations cluster within seven amino acids in one of the six possible cytosolic domains of ANK. These results suggest 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 increase mineralization.Harvard Sch Dent Med, Forsyth Inst, Harvard Forsyth Dept Oral Biol, Boston, MA 02115 USAHarvard Univ, Sch Med, Childrens Hosp, Dept Cell Biol, Boston, MA USAHarvard Univ, Sch Med, Childrens Hosp, Dept Genet, Boston, MA USAHarvard Univ, Sch Med, Childrens Hosp, Div Plast Surg, Boston, MA USAUniversidade Federal de São Paulo, EPM, Campinas, SP, BrazilInst Cirurg Plast Craniofacial SOBRAPAR, Campinas, SP, BrazilShowa Univ, Sch Med, Dept Plast & Reconstruct Surg, Tokyo 142, JapanVirginia Commonwealth Univ, Med Coll Virginia, Dept Human Genet, Richmond, VA 23298 USASt Louis Univ, Sch Med, Cardinal Glennon Childrens Hosp, Div Med Genet, St Louis, MO 63104 USAUniv Cape Town, Sch Med, Dept Human Genet, ZA-7925 Cape Town, South AfricaOhio State Univ, Coll Dent, Dept Orthodont, Columbus, OH 43210 USAChildrens Hosp, Dept Genet, Columbus, OH 43205 USAUniv Minnesota, Sch Dent, Dept Oral Biol & Genet, Minneapolis, MN 55455 USAUniversidade Federal de São Paulo, EPM, Campinas, SP, BrazilWeb of Scienc