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Gene Review

Atp7b  -  ATPase, Cu++ transporting, beta polypeptide

Mus musculus

Synonyms: Atp7a, Copper pump 2, Copper-transporting ATPase 2, WND, Wilson disease-associated protein homolog, ...
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Disease relevance of Atp7b


Psychiatry related information on Atp7b


High impact information on Atp7b

  • Deletion of the promoter region in the Atp7a gene of the mottled dappled mouse [7].
  • The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene [8].
  • A preliminary report (Mosier, D. E., R. J. Gulizia, S. M. Baird, D. D. Richman, D. B. Wilson, R. I. Fox, and T. J. Kipps, 1989. Blood. 74(Suppl. 1):52a) has suggested that such tumors resemble the EBV-positive malignancy, Burkitt's lymphoma [9].
  • Lymphocytes from tx-mutant mice have a definite and consistent pattern of reactivity in MLR [10].
  • This indicates that tx-mutant types are associated with certain H-2 haplotypes, and that members of any give complementation group share the same H-2 haplotype [10].

Chemical compound and disease context of Atp7b

  • Previously, we showed that the transport of Cu by PC12 pheochromocytoma cells and C6 glioma cells correlated with the expression of a Cu-transporting ATPase (Atp7a) that has been linked to Menkes disease [11].

Biological context of Atp7b


Anatomical context of Atp7b


Associations of Atp7b with chemical compounds

  • The coding sequence of WND cDNA from the tx mouse liver identified a single nucleotide difference between the normal DL mouse and the tx which is predicted to change methionine 1356 in the eighth transmembrane domain to valine [17].
  • Atp7a is required for these copper-dependent effects: Hippocampal neurons isolated from newborn Mo(br) mice reveal a marked sensitivity to endogenous glutamate-mediated NMDA receptor-dependent excitotoxicity in vitro, and mild hypoxic/ischemic insult to these mice in vivo results in significantly increased caspase 3 activation and neuronal injury [18].
  • A functional analysis showed that Cu efflux was blocked by the sulfhydryl reagent p-chloromercuribenzoate (p-CMB), a potential inhibitor of Atp7a function [11].
  • Substitution of isoleucine for valine at position 214 in the third extracellular region (the putative E-MuLV binding site) of the MDTF receptor molecule allows this molecule to function as a Mo-MuLV receptor (M.V. Eiden, K. Farrell, J. Warsowe, L. A. Mahan, and C. A. Wilson, J. Virol. 67:4056-4061, 1993) [19].
  • The X-ray crystal structure for mouse adenosine deaminase shows zinc in contact with the attacking water nucleophile using purine riboside as a transition-state inhibitor [Wilson, D. K., Rudolph, F. B., & Quiocho, F. A. (1991) Science 252, 1278-1284] [20].

Physical interactions of Atp7b

  • WND results in accumulation of copper and the copper and zinc-binding protein metallothionein (MT) in liver and other tissues, liver degeneration, and neurological dysfunction [21].
  • A 30 kDa Ni/Zn-binding polypeptide was found to be markedly decreased in the livers of the tx mice [22].

Other interactions of Atp7b

  • Wilson disease is an autosomal recessive disorder of hepatic copper metabolism caused by mutations in a gene encoding a copper-transporting P-type ATPase [12].
  • Inactivation of ATP7B (Wilson disease protein) by gene knock-out induces a striking shift in the expression of the ATP7B target protein, ceruloplasmin, from PN to Bergmann glia, where ATP7A (Menkes disease protein) is present [2].
  • Analysis of 80 interspecific backcross offspring was used to position Atp7b close to D8Mit3 and another ATPase locus, Atp4b, on mouse chromosome 8 [14].
  • Toxic milk (tx) mutant mice with abnormally high MT and copper accumulation were also assessed [23].
  • Copper loading of normal mice also decreased hepatic CAIIIA mRNA, suggesting that the decrease in CAIII mRNA in the tx mouse liver is a secondary consequence of the high copper levels in the liver [22].

Analytical, diagnostic and therapeutic context of Atp7b

  • Our results provide convincing evidence for defining the LEC rat as an animal model for Wilson disease [8].
  • With the use of immunohistochemistry, our study demonstrated that the ATP7B protein was mislocalized in the lactating tx mouse mammary gland, which would explain the inability of the tx mouse to secrete normal amounts of copper in milk [24].
  • To characterize further the biochemical basis of this defect, Western blots of tissue extracts from normal and tx mice were probed with various heavy-metal radioisotopes (63Ni. 65Zn and 64Cu) [22].
  • Confocal microscopy analysis showed that, in the lactating tx mammary gland, ATP7B was predominantly perinuclear in comparison with the diffuse, cytoplasmic localization of ATP7B in the lactating normal mammary gland [24].
  • METHODS: RT/PCR was used to test for the presence of Wilson and Menkes mRNAs in mouse and human retinas and retinal pigment epithelial cell lines [5].


  1. Effect of the toxic milk mutation (tx) on the function and intracellular localization of Wnd, the murine homologue of the Wilson copper ATPase. La Fontaine , S., Theophilos, M.B., Firth, S.D., Gould, R., Parton, R.G., Mercer, J.F. Hum. Mol. Genet. (2001) [Pubmed]
  2. The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. Barnes, N., Tsivkovskii, R., Tsivkovskaia, N., Lutsenko, S. J. Biol. Chem. (2005) [Pubmed]
  3. Cu2+ toxicity inhibition of mitochondrial dehydrogenases in vitro and in vivo. Sheline, C.T., Choi, D.W. Ann. Neurol. (2004) [Pubmed]
  4. Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. Buiakova, O.I., Xu, J., Lutsenko, S., Zeitlin, S., Das, K., Das, S., Ross, B.M., Mekios, C., Scheinberg, I.H., Gilliam, T.C. Hum. Mol. Genet. (1999) [Pubmed]
  5. Retinal localization and copper-dependent relocalization of the Wilson and Menkes disease proteins. Krajacic, P., Qian, Y., Hahn, P., Dentchev, T., Lukinova, N., Dunaief, J.L. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  6. Foreward:alpha-melanocyte stimulating hormone and the melanocortin receptors. Taylor, A. Cell. Mol. Biol. (Noisy-le-grand) (2006) [Pubmed]
  7. Deletion of the promoter region in the Atp7a gene of the mottled dappled mouse. Levinson, B., Packman, S., Gitschier, J. Nat. Genet. (1997) [Pubmed]
  8. The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene. Wu, J., Forbes, J.R., Chen, H.S., Cox, D.W. Nat. Genet. (1994) [Pubmed]
  9. Epstein-Barr virus (EBV)-associated lymphoproliferative disease in the SCID mouse model: implications for the pathogenesis of EBV-positive lymphomas in man. Rowe, M., Young, L.S., Crocker, J., Stokes, H., Henderson, S., Rickinson, A.B. J. Exp. Med. (1991) [Pubmed]
  10. Murine t factors: an association between alleles at t and at H-2. Levinson, J.R., McDevitt, H.O. J. Exp. Med. (1976) [Pubmed]
  11. Copper efflux from murine microvascular cells requires expression of the menkes disease Cu-ATPase. Qian, Y., Tiffany-Castiglioni, E., Welsh, J., Harris, E.D. J. Nutr. (1998) [Pubmed]
  12. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation. Payne, A.S., Kelly, E.J., Gitlin, J.D. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  13. Consequences of copper accumulation in the livers of the Atp7b-/- (Wilson disease gene) knockout mice. Huster, D., Finegold, M.J., Morgan, C.T., Burkhead, J.L., Nixon, R., Vanderwerf, S.M., Gilliam, C.T., Lutsenko, S. Am. J. Pathol. (2006) [Pubmed]
  14. Mapping of the mouse homologue of the Wilson disease gene to mouse chromosome 8. Reed, V., Williamson, P., Bull, P.C., Cox, D.W., Boyd, Y. Genomics (1995) [Pubmed]
  15. Essential roles in development and pigmentation for the Drosophila copper transporter DmATP7. Norgate, M., Lee, E., Southon, A., Farlow, A., Batterham, P., Camakaris, J., Burke, R. Mol. Biol. Cell (2006) [Pubmed]
  16. Expression in mouse kidney of membrane copper transporters Atp7a and Atp7b. Moore, S.D., Cox, D.W. Nephron (2002) [Pubmed]
  17. The toxic milk mouse is a murine model of Wilson disease. Theophilos, M.B., Cox, D.W., Mercer, J.F. Hum. Mol. Genet. (1996) [Pubmed]
  18. Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity. Schlief, M.L., West, T., Craig, A.M., Holtzman, D.M., Gitlin, J.D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Glycosylation-dependent inactivation of the ecotropic murine leukemia virus receptor. Eiden, M.V., Farrell, K., Wilson, C.A. J. Virol. (1994) [Pubmed]
  20. Catalytic mechanism of yeast adenosine 5'-monophosphate deaminase. Zinc content, substrate specificity, pH studies, and solvent isotope effects. Merkler, D.J., Schramm, V.L. Biochemistry (1993) [Pubmed]
  21. Reduction of copper and metallothionein in toxic milk mice by tetrathiomolybdate, but not deferiprone. Czachor, J.D., Cherian, M.G., Koropatnick, J. J. Inorg. Biochem. (2002) [Pubmed]
  22. Decreased carbonic anhydrase III levels in the liver of the mouse mutant 'toxic milk' (tx) due to copper accumulation. Grimes, A., Paynter, J., Walker, I.D., Bhave, M., Mercer, J.F. Biochem. J. (1997) [Pubmed]
  23. Regional brain distribution of metallothionein, zinc and copper in toxic milk mutant and transgenic mice. Ono, S., Koropatnick, D.J., Cherian, M.G. Toxicology (1997) [Pubmed]
  24. Defective localization of the Wilson disease protein (ATP7B) in the mammary gland of the toxic milk mouse and the effects of copper supplementation. Michalczyk, A.A., Rieger, J., Allen, K.J., Mercer, J.F., Ackland, M.L. Biochem. J. (2000) [Pubmed]
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