toxic milk


Gene Symbol: toxic milk
Description: ATPase, Cu++ transporting, beta polypeptide
Alias: Atp7a, WND, copper-transporting ATPase 2, Wilson protein, copper pump 2, toxic milk, wilson disease-associated protein homolog
Species: mouse
Products:     toxic milk

Top Publications

  1. Moore S, Cox D. Expression in mouse kidney of membrane copper transporters Atp7a and Atp7b. Nephron. 2002;92:629-34 pubmed
    ..Several copper proteins are required for copper homeostasis. ATP7A and ATP7B are genes encoding membrane copper transporters...
  2. Linz R, Barnes N, Zimnicka A, Kaplan J, Eipper B, Lutsenko S. Intracellular targeting of copper-transporting ATPase ATP7A in a normal and Atp7b-/- kidney. Am J Physiol Renal Physiol. 2008;294:F53-61 pubmed
    ..We demonstrate that two copper-transporting ATPases, ATP7A and ATP7B, contribute to this regulation...
  3. Huster D, Purnat T, Burkhead J, Ralle M, Fiehn O, Stuckert F, et al. High copper selectively alters lipid metabolism and cell cycle machinery in the mouse model of Wilson disease. J Biol Chem. 2007;282:8343-55 pubmed
    ..The identification of the network of specific copper-responsive targets facilitates further mechanistic analysis of human disorders of copper misbalance. ..
  4. Huster D, Finegold M, Morgan C, Burkhead J, Nixon R, Vanderwerf S, et al. Consequences of copper accumulation in the livers of the Atp7b-/- (Wilson disease gene) knockout mice. Am J Pathol. 2006;168:423-34 pubmed
    ..Our results suggest that the early effects of copper on cell genetic material contribute significantly to pathology associated with Atp7b inactivation. ..
  5. Buiakova O, Xu J, Lutsenko S, Zeitlin S, Das K, Das S, et al. Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. Hum Mol Genet. 1999;8:1665-71 pubmed
    ..In summary, inactivation of the murine ATP7B gene produces a form of cirrhotic liver disease that resembles Wilson disease in humans and the 'toxic milk' phenotype in the mouse.
  6. Rauch H. Toxic milk, a new mutation affecting cooper metabolism in the mouse. J Hered. 1983;74:141-4 pubmed
    b>Toxic milk, tx, a new autosomal recessive mutation in mice is described. Litters produced by mutant females display a syndrome including poor growth, hypopigmentation, tremors, and ultimately death at two weeks of age...
  7. Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S. The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum. J Biol Chem. 2005;280:9640-5 pubmed
    ..The copper-transporting ATPases ATP7A and ATP7B play a central role in distribution of copper in the central nervous system; genetic mutations in ATP7A ..
  8. Deng D, Ono S, Koropatnick J, Cherian M. Metallothionein and apoptosis in the toxic milk mutant mouse. Lab Invest. 1998;78:175-83 pubmed
    b>Toxic milk mutant (tx) mice accumulate excess copper (Cu) in liver with age and develop symptoms similar to those seen in human Wilson disease...
  9. Rauch H, Wells A. The toxic milk mutation, tx, which results in a condition resembling Wilson disease in humans, is linked to mouse chromosome 8. Genomics. 1995;29:551-2 pubmed

More Information


  1. Gray L, Peng F, Molloy S, Pendyala V, Muchenditsi A, Muzik O, et al. Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load. PLoS ONE. 2012;7:e38327 pubmed publisher
    ..These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion may contribute to an improved diagnosis and monitoring of WD. ..
  2. Grimes A, Paynter J, Walker I, Bhave M, Mercer J. Decreased carbonic anhydrase III levels in the liver of the mouse mutant 'toxic milk' (tx) due to copper accumulation. Biochem J. 1997;321 ( Pt 2):341-6 pubmed
    The mouse mutant 'toxic milk' (tx) is characterized by marked hepatic accumulation of copper, similar to that found in patients with the genetic disorder of copper transport, Wilson disease...
  3. Hirayama T, Van de Bittner G, Gray L, Lutsenko S, Chang C. Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model. Proc Natl Acad Sci U S A. 2012;109:2228-33 pubmed publisher
    ..The ability to monitor real-time copper fluxes in living animals offers potentially rich opportunities to examine copper physiology in health and disease. ..
  4. Kuo Y, Gitschier J, Packman S. Developmental expression of the mouse mottled and toxic milk genes suggests distinct functions for the Menkes and Wilson disease copper transporters. Hum Mol Genet. 1997;6:1043-9 pubmed
    ..The mouse homologues for the Menkes (MNK) and Wilson (WND) disease genes are the mottled (Atp7a) and toxic milk (Atp7b) genes, respectively...
  5. Linz R, Lutsenko S. Copper-transporting ATPases ATP7A and ATP7B: cousins, not twins. J Bioenerg Biomembr. 2007;39:403-7 pubmed
    ..places within the secretory pathway and is critically dependent on the activity of copper-transporting ATPases ATP7A or ATP7B...
  6. Koropatnick J, Cherian M. Metallothionein protein and mRNA in the toxic milk mouse. Biochem J. 1994;304:318-9 pubmed
  7. Mercer J, Paynter J, Grimes A. The toxic milk mouse does have elevated hepatic metallothionein mRNA. Biochem J. 1994;304 ( Pt 1):317-8 pubmed
  8. Leonhardt K, Gebhardt R, Mossner J, Lutsenko S, Huster D. Functional interactions of Cu-ATPase ATP7B with cisplatin and the role of ATP7B in the resistance of cells to the drug. J Biol Chem. 2009;284:7793-802 pubmed publisher
    ..The link between changes in copper homeostasis and cisplatin resistance was confirmed by treating the Huh7 cells with copper chelator and increasing their resistance to cisplatin.cisplatin. ..
  9. Morrison G, Semple C, Kilanowski F, Hill R, Dorin J. Signal sequence conservation and mature peptide divergence within subgroups of the murine beta-defensin gene family. Mol Biol Evol. 2003;20:460-70 pubmed
    ..This mechanism of evolution is consistent with the role of this gene family as defense against bacterial pathogens and the sequence changes have implications for novel antibiotic design. ..
  10. Voskoboinik I, Greenough M, La Fontaine S, Mercer J, Camakaris J. Functional studies on the Wilson copper P-type ATPase and toxic milk mouse mutant. Biochem Biophys Res Commun. 2001;281:966-70 pubmed
    The Wilson protein (WND; ATP7B) is an essential component of copper homeostasis. Mutations in the ATP7B gene result in Wilson disease, which is characterised by hepatotoxicity and neurological disturbances...
  11. Zhang J, Liu J, Hou H, Chen D, Feng L, Wu C, et al. Effects of tetrathiomolybdate and penicillamine on brain hydroxyl radical and free copper levels: a microdialysis study in vivo. Biochem Biophys Res Commun. 2015;458:82-5 pubmed publisher
    ..These results suggested that the further increased free copper in the brain and oxidative stress caused by some chelators might contribute to the neurological deterioration. ..
  12. Wooton Kee C, Jain A, Wagner M, Grusak M, Finegold M, Lutsenko S, et al. Elevated copper impairs hepatic nuclear receptor function in Wilson's disease. J Clin Invest. 2015;125:3449-60 pubmed publisher
    ..Together, these data demonstrate that copper-mediated nuclear receptor dysfunction disrupts liver function in WD and potentially in other disorders associated with increased hepatic copper levels. ..
  13. Tumer Z, Horn N. Menkes disease: recent advances and new insights into copper metabolism. Ann Med. 1996;28:121-9 pubmed
  14. Strader C, Fong T, Tota M, Underwood D, Dixon R. Structure and function of G protein-coupled receptors. Annu Rev Biochem. 1994;63:101-32 pubmed
  15. Lalioti V, Hernandez Tiedra S, Sandoval I. DKWSLLL, a versatile DXXXLL-type signal with distinct roles in the Cu(+)-regulated trafficking of ATP7B. Traffic. 2014;15:839-60 pubmed publisher
  16. Koropatnick J, Cherian M. A mutant mouse (tx) with increased hepatic metallothionein stability and accumulation. Biochem J. 1993;296 ( Pt 2):443-9 pubmed
    ..We report high hepatic MT protein accumulation (greater than 100-fold compared with wild-type mice) in toxic milk (tx) mice, along with markedly higher cytosol copper and zinc levels...
  17. Peng F, Lutsenko S, Sun X, Muzik O. Positron emission tomography of copper metabolism in the Atp7b-/- knock-out mouse model of Wilson's disease. Mol Imaging Biol. 2012;14:70-8 pubmed publisher
    ..The results suggest feasibility of utilizing ??CuCl? as a tracer for noninvasive assessment of copper metabolism in WD with PET. ..
  18. Roberts E, Robinson B, Yang S. Mitochondrial structure and function in the untreated Jackson toxic milk (tx-j) mouse, a model for Wilson disease. Mol Genet Metab. 2008;93:54-65 pubmed
    ..We examined the functional basis for these mitochondrial changes in the toxic milk (tx-j) mouse model for WD. Its normal syngeic strain, C3H, served as control...
  19. Materia S, Cater M, Klomp L, Mercer J, La Fontaine S. Clusterin (apolipoprotein J), a molecular chaperone that facilitates degradation of the copper-ATPases ATP7A and ATP7B. J Biol Chem. 2011;286:10073-83 pubmed publisher
    The copper-transporting P(1B)-type ATPases (Cu-ATPases) ATP7A and ATP7B are key regulators of physiological copper levels...
  20. Coronado V, Nanji M, Cox D. The Jackson toxic milk mouse as a model for copper loading. Mamm Genome. 2001;12:793-5 pubmed
  21. Dong Y, Shi S, Chen S, Ni W, Zhu M, Wu Z. The discrepancy between the absence of copper deposition and the presence of neuronal damage in the brain of Atp7b(-/-) mice. Metallomics. 2015;7:283-8 pubmed publisher
  22. Phinney A, Drisaldi B, Schmidt S, Lugowski S, Coronado V, Liang Y, et al. In vivo reduction of amyloid-beta by a mutant copper transporter. Proc Natl Acad Sci U S A. 2003;100:14193-8 pubmed
    ..These data suggest that the beneficial effect of the txJ mutation on CNS Abeta burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of Abeta peptide. ..
  23. Mercer J, Grimes A, Rauch H. Hepatic metallothionein gene expression in toxic milk mice. J Nutr. 1992;122:1254-9 pubmed
    The toxic milk mutation (tx) in mice is an autosomal recessive condition that causes a marked hepatic accumulation of copper in adults and severe copper deficiency in the pups of tx/tx dams...
  24. Muchenditsi A, Yang H, Hamilton J, Koganti L, Housseau F, Aronov L, et al. Targeted inactivation of copper transporter Atp7b in hepatocytes causes liver steatosis and obesity in mice. Am J Physiol Gastrointest Liver Physiol. 2017;313:G39-G49 pubmed publisher
    ..b>NEW & NOTEWORTHY Targeted inactivation of copper-transporting ATPase 2 (Atp7b) in hepatocytes causes steatosis in the absence of inflammation. ..
  25. He K, Chen Z, Ma Y, Pan Y. Identification of high-copper-responsive target pathways in Atp7b knockout mouse liver by GSEA on microarray data sets. Mamm Genome. 2011;22:703-13 pubmed publisher
    ..The results of our study may help us better understand the molecular mechanisms of high-copper effects in mice liver in genome-wide. ..
  26. Stephenson G, Chan H, Cherian M. Copper-metallothionein from the toxic milk mutant mouse enhances lipid peroxidation initiated by an organic hydroperoxide. Toxicol Appl Pharmacol. 1994;125:90-6 pubmed
    The toxic milk mutation is an autosomal recessive mutation found in an inbred C57BL/6J strain of mice which results in an excessive hepatic accumulation of copper (Cu), mostly associated with metallothionein (MT)...
  27. Lutsenko S. Atp7b-/- mice as a model for studies of Wilson's disease. Biochem Soc Trans. 2008;36:1233-8 pubmed publisher
  28. Howell J, Mercer J. The pathology and trace element status of the toxic milk mutant mouse. J Comp Pathol. 1994;110:37-47 pubmed
    The toxic milk (tx) mouse is a mutant in which copper metabolism is abnormal...
  29. Cecchi C, Avner P. Genomic organization of the mottled gene, the mouse homologue of the human Menkes disease gene. Genomics. 1996;37:96-104 pubmed
    ..gene has been shown to span 120 kb of genomic DNA and to be similar in structure to both its human MNK homologue (ATP7A) and the Wilson disease gene (WD; ATP7B)...
  30. Theophilos M, Cox D, Mercer J. The toxic milk mouse is a murine model of Wilson disease. Hum Mol Genet. 1996;5:1619-24 pubmed
    ..Mutations in a copper transporting ATPase (WND or ATP7B) have been shown to cause the disease. The toxic milk mouse mutant (tx) accumulates copper in the liver in a manner similar to that observed in patients with WD...
  31. Harris E, Qian Y, Reddy M. Genes regulating copper metabolism. Mol Cell Biochem. 1998;188:57-62 pubmed
  32. Biempica L, Rauch H, Quintana N, Sternlieb I. Morphologic and chemical studies on a murine mutation (toxic milk mice) resulting in hepatic copper toxicosis. Lab Invest. 1988;59:500-8 pubmed
    The accumulation of excessive amounts of copper in the livers of toxic milk mice results in gross morphologic, histologic, and ultrastructural changes that are progressive with age even though the concentrations of copper tend to decrease ..
  33. Chen D, Feng L, Lin X, Zhang W, Li F, Liang X, et al. Penicillamine increases free copper and enhances oxidative stress in the brain of toxic milk mice. PLoS ONE. 2012;7:e37709 pubmed publisher
    ..aim of this study was to determine how the copper metabolism changes and whether the change impairs the brain of toxic milk (tx) mice, an animal model of WD, during the PA administration...
  34. Ono S, Koropatnick D, Cherian M. Regional brain distribution of metallothionein, zinc and copper in toxic milk mutant and transgenic mice. Toxicology. 1997;124:1-10 pubmed
    ..b>Toxic milk (tx) mutant mice with abnormally high MT and copper accumulation were also assessed...
  35. Materia S, Cater M, Klomp L, Mercer J, La Fontaine S. Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. J Biol Chem. 2012;287:2485-99 pubmed publisher
    b>ATP7A and ATP7B are copper-transporting P(1B)-type ATPases (Cu-ATPases) that are critical for regulating intracellular copper homeostasis...
  36. Boaru S, Merle U, Uerlings R, Zimmermann A, Flechtenmacher C, Willheim C, et al. Laser ablation inductively coupled plasma mass spectrometry imaging of metals in experimental and clinical Wilson's disease. J Cell Mol Med. 2015;19:806-14 pubmed publisher
    ..We conclude that in Wilson's disease the imbalances of hepatic copper during ageing are closely correlated with alterations in intrahepatic iron and zinc content. ..
  37. Miyayama T, Hiraoka D, Kawaji F, Nakamura E, Suzuki N, Ogra Y. Roles of COMM-domain-containing 1 in stability and recruitment of the copper-transporting ATPase in a mouse hepatoma cell line. Biochem J. 2010;429:53-61 pubmed publisher
    ..e. COMMD1 is required to shuttle Atp7b when the intracellular copper level returns below the threshold...
  38. Terwel D, Löschmann Y, Schmidt H, Scholer H, Cantz T, Heneka M. Neuroinflammatory and behavioural changes in the Atp7B mutant mouse model of Wilson's disease. J Neurochem. 2011;118:105-12 pubmed publisher
    ..well as neuronal number, inflammatory markers, copper and synaptic proteins in brain were studied in so-called toxic milk mice. Copper accumulated in striatum and hippocampus of toxic milk mice, but not in cerebral cortex...
  39. Sebastiani G, Krzywkowski P, Dudal S, Yu M, Paquette J, Malo D, et al. Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice. Hum Mol Genet. 2006;15:2313-23 pubmed
    ..Further characterization of these QTL regions may lead to the identification of genes involved in the pathogenesis of AD. ..
  40. Lalioti V, Peiro R, Pérez Berlanga M, Tsuchiya Y, Muñoz Á, Villalba T, et al. Basolateral sorting and transcytosis define the Cu+-regulated translocation of ATP7B to the bile canaliculus. J Cell Sci. 2016;129:2190-201 pubmed publisher
    ..Our data reveal the pathway of the Cu(+)-mediated transport of ATP7B from the TGN to the bile canaliculus and indicates that the bile canaliculus is the primary site of ATP7B action in the elimination of excess Cu(.) ..
  41. Wilmarth P, Short K, Fiehn O, Lutsenko S, David L, Burkhead J. A systems approach implicates nuclear receptor targeting in the Atp7b(-/-) mouse model of Wilson's disease. Metallomics. 2012;4:660-8 pubmed publisher
  42. Gerbasi V, Lutsenko S, Lewis E. A mutation in the ATP7B copper transporter causes reduced dopamine beta-hydroxylase and norepinephrine in mouse adrenal. Neurochem Res. 2003;28:867-73 pubmed
    The copper-transporting ATPases Atp7A and Atp7B play a major role in controlling intracellular copper levels. In addition, they are believed to deliver copper to the copper-requiring proteins destined for the secretory vesicles...
  43. Reed V, Williamson P, Bull P, Cox D, Boyd Y. Mapping of the mouse homologue of the Wilson disease gene to mouse chromosome 8. Genomics. 1995;28:573-5 pubmed
    ..This assignment suggests a possible location for the toxic milk mutation in the mouse, which has been proposed as a homologue of WD.
  44. Michalczyk A, Bastow E, Greenough M, Camakaris J, Freestone D, Taylor P, et al. ATP7B expression in human breast epithelial cells is mediated by lactational hormones. J Histochem Cytochem. 2008;56:389-99 pubmed publisher
    ..Trafficking of ATP7B was copper dependent, suggesting that the hormone-induced redistribution of ATP7A was mediated through an increase in intracellular copper...
  45. Paynter J, Grimes A, Lockhart P, Mercer J. Expression of the Menkes gene homologue in mouse tissues lack of effect of copper on the mRNA levels. FEBS Lett. 1994;351:186-90 pubmed
    ..Results with copper-loaded normal mice and mutant mice with genetic defects in copper transport suggested that Mnk mRNA levels are not regulated by tissue copper concentrations. ..
  46. Roberts E, Lau C, da Silveira T, Yang S. Developmental expression of Commd1 in the liver of the Jackson toxic milk mouse. Biochem Biophys Res Commun. 2007;363:921-5 pubmed
    ..We examined developmental expression of Commd1 and Xiap in the Jackson toxic milk mouse (Atp7b(tx-J), G712D missense mutation in Atp7b)...
  47. Michalczyk A, Rieger J, Allen K, Mercer J, Ackland M. Defective localization of the Wilson disease protein (ATP7B) in the mammary gland of the toxic milk mouse and the effects of copper supplementation. Biochem J. 2000;352 Pt 2:565-71 pubmed
    b>Toxic milk (tx) is a copper disorder of mice that causes a hepatic accumulation of copper similar to that seen in patients with Wilson disease. Both disorders are caused by a defect in the ATP7B copper-transporting ATPase...