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

Am J Hum Genet. 2001 Jun;68(6):1321-6. doi: 10.1086/320612. Epub 2001 Apr 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Bone Diseases, Developmental / genetics*
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Chromosomes, Human, Pair 5 / genetics*
  • Cytosol / chemistry
  • DNA Mutational Analysis
  • Exons / genetics
  • Female
  • Genes, Dominant / genetics*
  • Genetic Linkage / genetics*
  • Humans
  • Lod Score
  • Male
  • 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


  • ANKH protein, human
  • Membrane Proteins
  • Phosphate Transport Proteins
  • RNA, Messenger

Associated data

  • OMIM/123000
  • OMIM/146300
  • OMIM/166500
  • OMIM/218300
  • OMIM/218400
  • OMIM/265900
  • OMIM/269500
  • OMIM/305620