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Gene Review

ANKH  -  ANKH inorganic pyrophosphate transport...

Homo sapiens

Synonyms: ANK, CCAL2, CMDJ, CPPDD, HANK, ...
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Disease relevance of ANKH


High impact information on ANKH

  • Sudden death in young athletes. Lessons from the Hank Gathers affair [5].
  • These results identify ANK-mediated control of pyrophosphate levels as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals [6].
  • Ankyrins are spectrin-binding proteins that associate via ANK repeats with a variety of ion channels/pumps, calcium release channels and cell adhesion molecules [7].
  • Mutations in the progressive ankylosis gene (Ank/ANKH) cause surprisingly different skeletal phenotypes in mice and humans [8].
  • Although most cases are sporadic, rare familial forms have been linked to human chromosomes 8 (CCAL1) or 5p (CCAL2) (Baldwin et al. 1995; Hughes et al. 1995; Andrew et al. 1999) [1].

Chemical compound and disease context of ANKH


Biological context of ANKH

  • METHODS: Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls [10].
  • RESULTS: We identified 2 novel polymorphic sites: one in the 5'-noncoding region of ANKH involving 1-2 copies of an 8-bp repeat (denoted as ANKH-OR), and the other in the promoter region involving different copy numbers of a triplet repeat (denoted as ANKH-TR) [3].
  • Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen [2].
  • The distinct disease haplotypes among the 3 families with P5 mutations suggest that the mutations arose independently and that the evolutionarily conserved P5 position of ANKH may represent a hot spot for mutation in families with autosomal-dominant CPPD [11].
  • RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02) [2].

Anatomical context of ANKH

  • This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro [2].
  • A number of human mutations have subsequently been reported in the human ortholog (ANKH), some of which produce skull and long bone defects with no apparent defects in joints or articular cartilage [12].
  • After adjustment for body height, we demonstrated the substantial association increase for biacromial breadth (P=0.0012; some 140 kb downstream from ANKH) and vertebral column length (P=0.0008; exons 2-7 region) [13].
  • 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 [14].
  • Each of the three human mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro [1].

Associations of ANKH with chemical compounds

  • ANKH encodes a putative transmembrane inorganic pyrophosphate (PPi) transport channel [9].
  • To determine the effect of ANK on more primitive long-term culture-initiating cells (LTCIC), the IL-2-supplemented LTBMC medium was replaced with fresh hydrocortisone containing LTBMC medium, and cultures were maintained for an additional 5 weeks [15].
  • We further demonstrate that the beta2 integrin receptor is involved in ANK recognition of CML targets [15].
  • Sensitivity to ABA of embryos was higher in grains collected around harvest-maturity for ANK lines and AUS 1490, compared with NS-67 and EMS-AUS [16].
  • Should Hank side with Charlie or Harriet [17]?

Other interactions of ANKH

  • Novel genetic markers in the 5'-flanking region of ANKH are associated with ankylosing spondylitis [3].
  • 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 [14].

Analytical, diagnostic and therapeutic context of ANKH

  • Direct coculture of purified NK and autologous monocytes in the same compartment, thus permitting cell-cell contact, resulted in significantly greater expansion of the ANK population (30.6 +/- 4.7-fold expansion, P < .001; n = 10) than that observed when NK and monocytes were separated by the Transwell membrane [18].
  • These observations support the use of autologous ANK therapy to prevent relapse of CML after autologous marrow transplantation or use of ANK to purge CML marrow for autologous transplantation [15].
  • In this study, we have designed a novel peptide (ANK) and shown its interaction with SNCG using fluorometry, surface plasmon resonance, and isothermal titration calorimetry [19].
  • However, maximal expansion of NK is also desired to facilitate clinical trials with large numbers of IL-2-activated NK (ANK) [20].
  • RECENT STUDIES: The two primary hypotheses for generation of ePPi, export of inorganic pyrophosphate through the multipass transmembrane protein ANK and generation of ePPi by ectoenzyme activity, continue to be supported and better understood through animal models and study of families with CPPD deposition disease [21].


  1. Mutations in ANKH cause chondrocalcinosis. Pendleton, A., Johnson, M.D., Hughes, A., Gurley, K.A., Ho, A.M., Doherty, M., Dixey, J., Gillet, P., Loeuille, D., McGrath, R., Reginato, A., Shiang, R., Wright, G., Netter, P., Williams, C., Kingsley, D.M. Am. J. Hum. Genet. (2002) [Pubmed]
  2. Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate. Zhang, Y., Johnson, K., Russell, R.G., Wordsworth, B.P., Carr, A.J., Terkeltaub, R.A., Brown, M.A. Arthritis Rheum. (2005) [Pubmed]
  3. Novel genetic markers in the 5'-flanking region of ANKH are associated with ankylosing spondylitis. Tsui, F.W., Tsui, H.W., Cheng, E.Y., Stone, M., Payne, U., Reveille, J.D., Shulman, M.J., Paterson, A.D., Inman, R.D. Arthritis Rheum. (2003) [Pubmed]
  4. Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nürnberg, P., Thiele, H., Chandler, D., Höhne, W., Cunningham, M.L., Ritter, H., Leschik, G., Uhlmann, K., Mischung, C., Harrop, K., Goldblatt, J., Borochowitz, Z.U., Kotzot, D., Westermann, F., Mundlos, S., Braun, H.S., Laing, N., Tinschert, S. Nat. Genet. (2001) [Pubmed]
  5. Sudden death in young athletes. Lessons from the Hank Gathers affair. Maron, B.J. N. Engl. J. Med. (1993) [Pubmed]
  6. Role of the mouse ank gene in control of tissue calcification and arthritis. Ho, A.M., Johnson, M.D., Kingsley, D.M. Science (2000) [Pubmed]
  7. Ankyrins and cellular targeting of diverse membrane proteins to physiological sites. Bennett, V., Chen, L. Curr. Opin. Cell Biol. (2001) [Pubmed]
  8. Biochemical and genetic analysis of ANK in arthritis and bone disease. Gurley, K.A., Reimer, R.J., Kingsley, D.M. Am. J. Hum. Genet. (2006) [Pubmed]
  9. Autosomal dominant familial calcium pyrophosphate dihydrate deposition disease is caused by mutation in the transmembrane protein ANKH. Williams, C.J., Zhang, Y., Timms, A., Bonavita, G., Caeiro, F., Broxholme, J., Cuthbertson, J., Jones, Y., Marchegiani, R., Reginato, A., Russell, R.G., Wordsworth, B.P., Carr, A.J., Brown, M.A. Am. J. Hum. Genet. (2002) [Pubmed]
  10. Investigation of the role of ANKH in ankylosing spondylitis. Timms, A.E., Zhang, Y., Bradbury, L., Wordsworth, B.P., Brown, M.A. Arthritis Rheum. (2003) [Pubmed]
  11. Mutations in the amino terminus of ANKH in two US families with calcium pyrophosphate dihydrate crystal deposition disease. Williams, C.J., Pendleton, A., Bonavita, G., Reginato, A.J., Hughes, A.E., Peariso, S., Doherty, M., McCarty, D.J., Ryan, L.M. Arthritis Rheum. (2003) [Pubmed]
  12. Mineral formation in joints caused by complete or joint-specific loss of ANK function. Gurley, K.A., Chen, H., Guenther, C., Nguyen, E.T., Rountree, R.B., Schoor, M., Kingsley, D.M. J. Bone Miner. Res. (2006) [Pubmed]
  13. Strong association between polymorphisms in ANKH locus and skeletal size traits. Malkin, I., Ermakov, S., Kobyliansky, E., Livshits, G. Hum. Genet. (2006) [Pubmed]
  14. Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. Reichenberger, E., Tiziani, V., Watanabe, S., Park, L., Ueki, Y., Santanna, C., Baur, S.T., Shiang, R., Grange, D.K., Beighton, P., Gardner, J., Hamersma, H., Sellars, S., Ramesar, R., Lidral, A.C., Sommer, A., Raposo do Amaral, C.M., Gorlin, R.J., Mulliken, J.B., Olsen, B.R. Am. J. Hum. Genet. (2001) [Pubmed]
  15. Autologous activated natural killer cells suppress primitive chronic myelogenous leukemia progenitors in long-term culture. Cervantes, F., Pierson, B.A., McGlave, P.B., Verfaillie, C.M., Miller, J.S. Blood (1996) [Pubmed]
  16. Effect of grain colour gene (R) on grain dormancy and sensitivity of the embryo to abscisic acid (ABA) in wheat. Himi, E., Mares, D.J., Yanagisawa, A., Noda, K. J. Exp. Bot. (2002) [Pubmed]
  17. When salaries aren't secret. Case, J. Harvard business review. (2001) [Pubmed]
  18. Role of monocytes in the expansion of human activated natural killer cells. Miller, J.S., Oelkers, S., Verfaillie, C., McGlave, P. Blood (1992) [Pubmed]
  19. Synuclein-gamma targeting peptide inhibitor that enhances sensitivity of breast cancer cells to antimicrotubule drugs. Singh, V.K., Zhou, Y., Marsh, J.A., Uversky, V.N., Forman-Kay, J.D., Liu, J., Jia, Z. Cancer Res. (2007) [Pubmed]
  20. Production of human natural killer cells for adoptive immunotherapy using a computer-controlled stirred-tank bioreactor. Pierson, B.A., Europa, A.F., Hu, W.S., Miller, J.S. Journal of hematotherapy. (1996) [Pubmed]
  21. Modulation of chondrocyte production of extracellular inorganic pyrophosphate. Costello, J.C., Ryan, L.M. Current opinion in rheumatology. (2004) [Pubmed]
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