Autosomal Dominant Craniometaphyseal Dysplasia Is Caused by Mutations in the Transmembrane Protein ANK

• Published in: American journal of human genetics Vol. 68; no. 6; pp. 1321 - 1326
• Main Authors: Reichenberger, Ernst, Tiziani, Valdenize, Watanabe, Shoji, Park, Lucy, Ueki, Yasuyoshi, Santanna, Carla, Baur, Scott T., Shiang, Rita, Grange, Dorothy K., Beighton, Peter, Gardner, Jessica, Hamersma, Herman, Sellars, Sean, Ramesar, Rajkumar, Lidral, Andrew C., Sommer, Annmarie, Raposo do Amaral, Cassio M., Gorlin, Robert J., Mulliken, John B., Olsen, Bjorn R.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.06.2001; University of Chicago Press; The American Society of Human Genetics
• Subjects: Amino Acid Sequence; ANK protein; Base Sequence; Biological and medical sciences; Bone Diseases, Developmental - genetics; Cells, Cultured; Child; Child, Preschool; chromosome 5; Chromosomes, Human, Pair 5 - genetics; Craniometaphyseal dysplasia; Cytosol - chemistry; Diseases of the osteoarticular system; DNA Mutational Analysis; Exons - genetics; Female; Genes, Dominant - genetics; Genetic Linkage - genetics; Humans; Lod Score; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Membrane Proteins - chemistry; Membrane Proteins - genetics; Molecular Sequence Data; Mutation - genetics; Osteoblasts - metabolism; Pedigree; Phosphate Transport Proteins; Protein Structure, Tertiary; RNA, Messenger - analysis; RNA, Messenger - genetics; Human; Transmembrane protein; Family study; Pathogenesis; Diseases of the osteoarticular system; Genetic determinism; Genetic disease; Craniometaphyseal dysplasia; Gene; Membrane transport; Autosomal character; Dominant character; Diphosphates; Mutation; Osteochondrodysplasia
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/320612

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.