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

Ernst Reichenberger, Valdenize Tiziani, Shoji Watanabe, Lucy Park, Yasuyoshi Ueki, Carla Santanna, Scott T. Baur, Rita Shiang, Dorothy K. Grange, Peter Beighton, Jessica Gardner, Herman Hamersma, Sean Sellars, Rajkumar Ramesar, Andrew C. Lidral, Annmarie Sommer, Cassio M. Raposo do Amaral, Robert J. Gorlin, John B. Mulliken, Bjorn R. Olsen

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149 Scopus citations


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 ∼5-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.

Original languageEnglish
Pages (from-to)1321-1326
Number of pages6
JournalAmerican journal of human genetics
Issue number6
StatePublished - 2001


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