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

Abstract

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 approximately 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.

Loss of equilibrative nucleoside transporter 1 in mice leads to progressive ectopic mineralization of spinal tissues resembling diffuse idiopathic skeletal hyperostosis in humans

“…Ank is a transmembrane protein that is thought to mediate PP i transport. In mice, loss-offunction mutations of Ank lead to arthritis, ectopic crystal formation, and generalized joint fusion, (51) whereas, in humans, dominant mutations are associated with craniometaphyseal dysplasia (52,53) and familial chondrocalcinosis. (54,55) Thus, like Enpp1, decreased Ank expression in the spinal tissues of ENT1 -/-mice would be expected to further suppress extracellular PP i levels, permitting the formation of ectopic mineral deposits.…”

Pyrophosphate: a key inhibitor of mineralisation

“…At present, the biological role and function of ANK remains unclear. Although mutations are found in patients with 'pyrophosphate' diseases such as chondrocalcinosis [29,30], loss of function mutations are also found in other skeletal disorders, notably craniometaphysial dysplasia (CMD) [31,32]. This autosomal dominant condition is characterised by abnormal bone mineralisation leading to craniofacial bone thickening, widened long-bone metaphyses and increased cortical thickness.…”

Calcium Signalling and Calcium Transport in Bone Disease

“…It is a pyrophosphate transporter, so presumably the source of the pyrophosphate is intracellular although the biochemical pathway is unknown. Mutations in its human homolog, ANKH, cause a group of diseases including craniometaphysial dysplasia and chondrocalcinosis [Reichenberger et al, 2001;Nurnberg et al, 2001;Williams et al, 2002;Pendleton et al, 2002].…”