Wilson’s disease: A comprehensive review of the molecular mechanisms

International Journal of Molecular Sciences

Volumn 16, Issue 3, 2015, Pages 6419-6431

  Wu, Fei ^a   Wang, Jing ^b   Pu, Chunwen ^c   Qiao, Liang ^d   Jiang, Chunmeng ^b  

^a DALIAN UNIVERSITY   (China)

^b DALIAN MEDICAL UNIVERSITY   (China)

^c Department of Biobank the Sixth People s Hospital of Dalian   (China)

^d UNIVERSITY OF SYDNEY   (Australia)

Author keywords

ATP7B gene; Copper metabolism; Molecular mechanism; Wilson s disease

Indexed keywords

COPPER; COPPER EXPORTING ADENOSINE TRIPHOSPHATASE; PEROXIREDOXIN 3; PHOSPHATIDIC ACID; S ADENOSYLMETHIONINE; ADENOSINE TRIPHOSPHATASE; CATION TRANSPORT PROTEIN; WILSON DISEASE PROTEIN;

CELL PROLIFERATION; CELL TRANSFORMATION; COPPER METABOLISM; DNA METHYLATION; DOWN REGULATION; ENZYME PHOSPHORYLATION; ENZYME REGULATION; GENE EXPRESSION; GENE MUTATION; GENETIC CODE; GENETIC VARIABILITY; HIGH PERFORMANCE THIN LAYER CHROMATOGRAPHY; HOMEOSTASIS; HUMAN; ION TRANSPORT; LIVER INJURY; METAL BINDING; PHENOTYPE; PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; WILSON DISEASE; ANIMAL; BIOLOGICAL MODEL; GENETICS; METABOLISM; PATHOLOGY;

ADENOSINE TRIPHOSPHATASES; ANIMALS; CATION TRANSPORT PROTEINS; HEPATOLENTICULAR DEGENERATION; HUMANS; MODELS, BIOLOGICAL;

EID: 84925875084     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms16036419     Document Type: Review

References (84)

1. Wilson, S.A.K. Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of liver. Brain 1912, 34, 295–507.
2. Beinhardt, S.; Leiss, W.; Stattermayer, A.F.; Graziadei, I.; Zoller, H.; Stauber, R.; Maieron, A.; Datz, C.; Steindl-Munda, P.; Hofer, H. et al. Long-term outcomes of patients with Wilson disease in a large Austrian cohort. Clin. Gastroenterol. Hapatol. 2014, 12, 683–689.
3. Seniow, J.; Mroziak, B.; Czlonkowska, A.; Jedryka-Goral, A. Self-rated emotional functioning of patients with neurological or asymptomatic form of Wilson’s disease. J. Clin. Neuropsychol. 2004, 17, 367–373.
4. Zimbrean, P.C.; Schilsky, M.L. Psychiatric aspects of Wilson disease: A review. Gen. Hosp. Psychiatry 2014, 36, 53–62.
5. Roberts, E.A.; Schilsky, M.L. A practice guideline on Wilson disease. Hepatology 2003, 37, 1475–1492.
6. Gouider-Khouja, N. Wilson’s disease. Parkinsonism Relat. Disord. 2009, 15, 126–129.
7. Dong, Q.Y.; Wu, Z.Y. Advance in the pathogenesis and treatment of Wilson disease. Transl. Neurodegener. 2012, doi:10.1186/2047-9158-1-23.
8. Mehta, R.; Templeton, D.; O’brien, P.J. Mitochondrial involvement in genetically determined transition metal toxicity. II. Copper toxicity. Chem. Biol. Interact. 2006, 163, 77–85.
9. Roberts, E.A.; Robinson, B.H.; 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.
10. Ala, A.; Walker, A.P.; Ashkan, K.; Dooley, J.S.; Schilsky, M.L. Wilson’s disease. Lancet 2007, 369, 397–408.
11. Roberts, E.A. Wilson’s disease. Medicine 2011, 39, 602–604.
12. Tanzi, R.E.; Petrukhin, K.; Chernov, I.; Pellequer, J.L.; Wasco, W.; Ross, B.; Romano, D.M.; Pavone, L.; Brzustowicz, L.M. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. J. Nat. Genet. 1993, 5, 344–350.
13. Walker, J.M.; Tsivkovskii, R.; Lutsenko, S. Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson’s disease protein and regulates its catalytic activity. J. Biol. Chem. 2002, 277, 27953–27959.
14. Fatemi, N.; Sarkar, B. Molecular mechanism of copper transport in Wilson disease. Environ. Health Perspect. 2002, 110, 695–698.
15. Walker, J.M.; Huster, D.; Ralle, M.; Morgan, C.T.; Blackburn, N.J.; Lutsenko, S. The N-terminal metal-binding site 2 of the Wilson’s disease protein plays a key role in the transfer of copper from Atox1. J. Biol. Chem. 2004, 279, 15376–15384.
16. Cater, M.A.; La Fontaine, S.; Cox, D.; Mercer, J.F. Intracellular trafficking of the human Wilson protein: The role of the six N-terminal metal-binding sites. J. Biochem. 2004, 380, 805–813.
17. Cater, M.A.; La Fontaine, S.; Mercer, J.F.B. Copper binding to the N-terminal metal-binding sites or the CPC motif is not essential for copper-induced trafficking of the human Wilson protein (ATP7B). Biochem. J. 2007, 401, 143–153.
18. Huster, D.; Lusenko, S. The distinct roles of the N-terminal copper-binding sites in regulation of catalytic activity of the Wilson’s disease protein. J. Biol. Chem. 2003, 278, 32212–32218.
19. Lenartowicz, M.; Krzeptowski, W. Structure and function of ATP7A and ATP7B proteins—Cu-transporting ATPase. Postepy Biochem. 2010, 56, 317–327.
20. Lutsenko, S.; Efremov, R.G.; Tsivkovski, R.; Walker, J.M. Human copper-transporting ATPase ATP7B (the Wilson’s disease protein): Biochemical properties and regulation. J. Bioenerg. Biomembr. 2002, 34, 351–362.
21. Myari, A.; Hadjiliadis, N.; Fatemi, N.; Sarkar, B. Copper (I) interaction with model peptides of WD6 and TM6 domains of Wilson ATPase: Regulatory and mechanistic implications. J. Inorg. Biochem. 2004, 98, 1483–1494.
22. Tsivkovskii, R.; MacArthur, B.C.; Lutsenko, S. The Lys1010-Lys1325 fragment of the Wilson’s disease protein binds nucleotides and interacts with the N-terminal domain of this protein in a copper-dependent manner. J. Biol. Chem. 2001, 19, 2334–2342.
23. Dmitriev, O.; Tsivkoskii, R.; Abildgaard, F.; Morgan, C.T.; Markley, H.L.; Lutsenko, S. Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations. Proc. Natl. Acad. Sci. USA 2006, 103, 5302–5307.
24. Sazinsky, M.H.; Mandal, A.K.; Arguello, J.M.; Rosenzweig, A.C. Structure of the ATP bind domain from the Archaeoglobus fulgidus Cu+-ATPase. J. Biol. Chem. 2006, 281, 11161–11166.
25. Miller, J.V.; Juul, B.; Maire, M. Structural organization, ion transport, and energy transduction of P-type ATPases. Biochim. Biophys. Acta 1996, 1286, 1–51.
26. Petris, M.J.; Voskoboinik, I.; Cater, M.; Smith, K.; Kim, B.E.; Llanos, R.M.; Strausak, D.; Camakaris, J.; Mercer, J.F.B. Copper-regulated trafficking of the Menkes disease copper ATPase is associated with formation of a phosphorylated catalytic intermediate. J. Biol. Chem. 2002, 277, 46736–46742.
27. Moller, L.B.; Ott, P.; Lund, C.; Horn, N. Homozygosity for a gross partial gene deletion of the C-terminal end of ATP7B in a Wilson patient with hepatic and no neurological manifestations. Am. J. Med. Genet. 2005, 138, 340–343.
28. Huster, D.; Hoppert, M.; Lutsenko, S.; Zinke, J.; Lehmann, C.; Mossner, J.; Berr, F.; Caca, K. Defective cellular localization of mutant ATP7B in Wilson’s disease patients and hepatoma cell lines. Gastroenterology 2003, 124, 335–345.
29. Lutsenko, S.; Tsivkovskii, R.; Walker, J.M. Functional properties of the human copper-transporting ATPase ATP7B (the Wilson’s disease protein) and regulation by metallochaperone Atox1. Ann. N. Y. Acad. Sci. 2003, 986, 204–211.
30. Hung, I.H.; Suzuki, M.; Yamaguchi, Y.; Yuan, D.S.; Klausner, R.D.; Gitlin, J.D. Biochemical characterization of the Wilson disease protein and function expression in the yeast Saccharomyces cerevisiae. J. Biol. Chem. 1997, 272, 21461–21466.
31. Harada, M.; Kawaguchi, T.; Kumemura, H.; Terada, K.; Ninomiya, H.; Taniquchi, E.; Hanada, S.; Maeyama, M.; Koqa, H.; Ueno, T. et al. The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein. Am. J. Pathol. 2005, 166, 499–510.
32. Gitlin, J.D. Copper homeostasis: Specialized functions of the late secretory pathway. Dev. Cell 2014, 29, 631–632.
33. Chen, H.R.; Yang, H.C.; Hsieh, D.J.; Liu, Z.; Tsai, K.J. Zebrafish sod1 and sp1 expression are modulated by the copper ATPase gene atp7a in response to intracellular copper status. Chem. Biol. Interact. 2011, 189, 192–197.
34. Zhou, B.; Gitschier, J. hCTR1: A human gene for copper uptake identified by complementation in yeast. Proc. Natl. Acad. Sci. USA 1997, 94, 7481–7486.
35. Hellman, N.E.; Kono, S.; Mancini, G.M.; Hoogeboom, A.J.; de Jong, G.J.; Gitlin, J.D. Mechanisms of copper incorporation into human ceruloplasmin. J. Biol. Chem. 2002, 277, 46632–46638.
36. Polishchuk, E.V.; Concilli, M.; Iacobacci, S.; Chesi, G.; Pastore, N.; Piccolo, P.; Paladino, S.; Baldantoni, D.; van IJzendoorn, S.C.; Chan, J. et al. Wilson disease protein ATP7B utilized lysosomal exocytosis to maintain copper homeostasis. Dev. Cell 2014, 29, 686–700.
37. Cater, M.; la Fontaine, S.; Shield, K.; Deal, Y.; Mercer, F.B.J. ATP7B mediates vesicular sequestration of copper; Insight into biliary copper excretion. Gastroenterology 2006, 130, 493–506.
38. Kucinskas, L.; Jeroch, J.; Vitkauskiene, A.; Sakalauskas, R.; Petrenkiene, V.; Kucinskas, V.; Naginiene, R.; Schmidt, H.; Kupcinskas, L. High frequency of the c.3207C>A (p.H1069Q) mutation in ATP7B gene of Lithuanian patients with hepatic presentation of Wilson’s disease. World J. Gastroenterol. 2008, 14, 5876–5879.
39. Gromadzka, G.; Schmidt, H.H.; Genschel, J.; Bochow, B.; Rodo, M.; Tarnacka, B.; Litwin, T.; Chabik, G.; Czonkowska, A. Frameshift and nonsense mutations in the gene for ATPase are associated with sever impairment of copper metabolism and with an early clinical manifestation of Wilson’s disease. Clin. Genet. 2005, 68, 524–532.
40. Cox, D.W.; Fraser, F.C.; Sass-Kortsak, A. A genetic study of Wilson’s disease: Evidence for heterogeneity. Am. J. Hum. Genet. 1972, 24, 646–666.
41. Lepori, M.B.; Zappu, A.; Incollu, S.; Dessi, V.; Mameli, E.; Demelia, L.; Nurchi, A.M.; Gheorghe, L.; Maggiore, G.; Sciveres, M. et al. Mutation analysis of the ATP7B gene in a new group of Wilson’s disease patients: Contribution to diagnosis. Mol. Cell. Probes 2012, 26, 147–150.
42. Roberts, E.A.; Schilky, M.L. Diagnosis and treatment of Wilson disease: An update. Hepatology 2008, 47, 2089–2111.
43. Gupta, A.; Chattopadhyay, I.; Dey, S.; Nasipuri, P.; Das, S.K.; Gangopadhyay, P.K.; Ray, K. Molecular pathogenesis of Wilson disease among Indians: A perspective on mutation spectrum in ATP7B gene, prevalent defects, clinical heterogeneity and implication toward diagnosis. Cell. Mol. Neurobiol. 2007, 27, 1023–1033.
44. Usta, J.; Daya, H.A.; Halawi, H.; Al-Shareef, I.; EI-Rifai, O.; Malli, A.H.; Sharara, A.I.; Habib, R.H.; Barada, K. Homozygosity for non-H1069Q missense mutation in ATP7B gene and early severe liver disease: Report of two families and a meta-analysis. JIMD Rep. 2012, 4, 129–137.
45. Sokol, R.J.; Twedt, D.; Mckim, J.M.; Devereaux, M.W.; Karrer, F.M.; Kam, I.; Steiqman, G.; Narkewicz, M.R.; Bacon, B.P.; Britton, R.S. Oxidant injury to hepatic mitochondria in patients with Wilson’s disease and bedlington terriers with copper toxicosis. Gastroenterology 1994, 107, 1788–1798.
46. Rossi, L.; Lombardo, M.F.; Ciriolo, M.R.; Rotillo, G. Mitochondral dysfunction in neurodegenerative disease associated with copper imbalance. Neurochem. Res. 2004, 29, 493–504.
47. Sauer, S.W.; Merle, E.; Opp, S.; Haas, D.; Hoffmann, G.F.; Stremmel, W.; Okun, J.G. Severe dysfunction of respiratory chain and cholesterol metabolism in Atp7b−/− mice as a model for Wilson disease. Biochim. Biophys. Acta 2011, 1812, 1607–1615.
48. Arnarez, C.; Mazat, J.P.; Elezgaray, J.; Marrink, S.J.; Periole, X. Evidence for cardiolipin binding sites on the membrane-exposed surface of the cytochrome bc1. J. Am. Chem. Soc. 2013, 135, 3112–3120.
49. Petrosillo, G.; Ruggiero, F.M.; Paradies, G. Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria. FAEB J. 2003, 17, 2202–2208.
50. Montero, J.; Mari, M.; Collell, A.; Morales, A.; Basanez, G.; Garcia-Ruiz, C.; Femandez-Checa, J.C. Cholesterol and peroxidized cardiolipin in mitochondrial membrane properties, permeabilization and cell death. Biochim. Biophys. Acta 2010, 1797, 1217–1224.
51. Shadyro, O.I.; Yurkova, I.L.; Kisel, M.A.; Brede, O.; Arnhold, J. Formation of phosphatidic acid,ceramide and diglyceride on radiolysis of lipids: Identification by MALDI-TOF mass spectrometry. Free Radic. Biol. Med. 2004, 36, 1612–1624.
52. Yurkova, I.L.; Stuckert, F.; Kisel, M.A.; Shadyro, O.I.; Arnhold, J.; Huster, D. Formation of phosphatidic acid in stressed mitochondria. Arch. Biochem. Biophys. 2008, 480, 17–26.
53. Yurkova, I.L.; Arnhold, J.; Fitzl, G.; Huster, D. Fragmentation of mitochondrial cardiolipin by copper ions in the Atp7b−/− mouse model of Wilson’s disease. Chem. Phys. Lipids 2011, 164, 393–400.
54. Liu, Y.; Su, Y.; Wang, X.M. Phosphatidic acid-mediated signaling. Adv. Exp. Med. Biol. 2013, 991, 159–176.
55. Kroemer, G.; Reed, J.C. Mitochondrial control of cell death. Nat. Med. 2000, 6, 513–519.
56. Zischka, H.; Lichtmannegger, J.; Schmitt, S.; Jagemamm, N.; Schulz, S.; Wartini, D.; Jennen, L.; Rust, C.; Larochette, N.; Galluzzi, L. et al. Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease. J. Clin. Investig. 2011, 121, 1508–1518.
57. Huster, D. Structural and metabolic changes in Atp7b−/− mouse liver and potential for new interventions in Wilson’s disease. Ann. N. Y. Acad. Sci. 2014, 1315, 37–44.
58. Czlonkowska, A.; Gromadzka, G.; Chabik, G. Monozygotic female twins discordant for phenotype of Wilson’s disease. Mov. Disord. 2009, 24, 1066–1069.
59. Ferenci, P. Polymorphism of methylenetetrahydrofolate reductase as disease modifier—A deja-vu in Wilson disease? J. Hepatol. 2011, 55, 753–755.
60. Litwin, T.; Gromadzka, G.; Czlonkowska, A. Apolipoprotein E gene (APOE) genotype in Wilson’s disease: Impact on clinical presentation. Parkinsonism Relat. Disord. 2012, 18, 367–369.
61. Cocos, R.; Sendroiu, A.; Schipor, S.; Bohitea, L.C.; Sendroiu, I. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson’s disease: Genetic and clinical homogeneity. PLoS One 2014, 9, e98520.
62. Okada, T.; Shiono, Y.; Hayashi, H.; Satoh, H.; Sawada, T.; Suzuki, A.; Takeda, Y.; Yano, M.; Michitaka, K.; Onji, M. et al. Mutational analysis of ATP7B and genotype-phenotype correlation in Japanese with Wilson’s disease. Hum. Mutat. 2000, 15, 454–462.
63. Liu, X.Q.; Zhang, Y.F.; Liu, T.T.; Hsiao, K.J.; Zhang, J.M.; Gu, X.F.; Bao, K.R.; Yu, L.H.; Wang, M.X. Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World J. Gastroenterol. 2004, 15, 590–593.
64. Lee, B.H.; Kin, J.H.; Lee, S.Y.; Jin, H.Y.; Kim, K.J. Distinct clinical courses according to presenting phenotypes and their correlations to ATP7B mutations in a large Wilson’s disease cohort. Liver Int. 2011, 31, 831–839.
65. Krijt, J.; Duta, A.; Kozich, V. Determination of S-adenosylmethionine and S-adenosylhomocysteine by LC-MS/MS and evaluation of their stability in mice tissues. J. Chromatogr. B 2009, 877, 2061–2966.
66. Le, A.; Shibata, N.M.; French, S.W.; Kim, K.; Kharbanba, K.K.; Islam, M.S.; LaSalle, J.M.; Halsted, C.H.; Keen, C.L.; Medici, V. Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease. Int. J. Mol. Sci. 2014, 15, 8004–8023.
67. Tao, J.; Yang, M.; Chen, Z.; Huang, Y.; Zhao, Q.; Xu, J.; Ren, H.; Zhao, H.; Chen, Z.; Ren, Q. et al. Decreased DNA methyltransferase 3A and 3B mRNA expression in peripheral blood mononuclear cells and increased plasma SAH concentration in adult patients with idiopathic thrombocytopenic purpura. J. Clin. Immunol. 2008, 28, 432–439.
68. Medici, V.; Shibata, N.M.; Kharbanda, K.K.; LaSalle, J.M.; Woods, R.; Liu, S.; Engelberg, J.A.; Devaraj, S.; Torok, N.J.; Jiang, J.X. et al. Wilson’s disease: Changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology 2013, 57, 555–565.
69. Oh, B.K.; Kim, H.; Park, H.J.; Shim, Y.H.; Choi, J.; Park, C.; Park, Y.N. DNA methyltransferase expression and DNA methylation in human hepatocellular carcinoma and their clinicopathological correlation. Int. J. Mol. Med. 2007, 20, 65–73.
70. Levy, E.; Brunet, S.; Alvarez, F.; Seidman, E.; Bouchard, G.; Escobar, E.; Martin, S. Abnormal hepatobiliary and circulating lipid metabolism in the Long-Evans Cinnamon rat model of Wilson’s disease. Life Sci. 2007, 16, 1472–1483.
71. Huster, D.; Purnat, T.D.; Burkhead, J.L.; Ralle, M.; Fiehn, O.; Stuckert, F.; Olson, N.E.; Teupser, D.; Lutsenko, S. High copper selectively alters lipid metabolism and cell cycle machinery in the mouse model of Wilson disease. J. Biol. Chem. 2007, 282, 8343–8355.
72. European association for the study of the liver. EASL Clinical Practice Guidelines: Wilson’s disease. J. Hepatol. 2012, 56, 671–685.
73. Burkhead, J.L.; Gray, L.W.; Lutsenko, S. Systems biology approach to Wilson’s disease. Biometals 2011, 24, 455–466.
74. Bennett, J.; Hahn, S.H. Clinical molecular diagnosis of Wilson disease. Semin. Liver Dis. 2011, 31, 233–238.
75. Bennett, J.T.; Schwarz, K.B.; Swanson, P.D.; Hahn, S.H. An exceptional family with three consecutive generations affected by Wilson disease. JIMD Rep. 2013, 10, 1–4.
76. Brewer, G.J. Diagnosis of Wilson’s disease. Neth. J. Med. 2009, 67, 195.
77. Purchase, R. The treatment of Wilson’s disease, a rare genetic disorder of copper metabolism. Sci. Prog. 2013, 96, 19–32.
78. Askari, F.K.; Greenson, G.; Dick, R.D.; Johnson, V.D.; Brewre, G.J. Treatment of Wilson’s disease with zinc.XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc. J. Lab. Clin. Med. 2003, 142, 385–390.
79. Ala, A.; Borjigin, J.; Rochwarger, A.; Schilsky, M. Wlison disease in septuagenarian siblings: Raising the bar for diagnosis. Hepatology 2005, 41, 668–670.
80. Marin, C.; Robles, R.; Parrilla, G.; Ramirez, P.; Bueno, F.S.; Parrilla, P. Liver transplantation in Wilson’s disease: Are its indications established? Transplant. Proc. 2007, 39, 2300–2301.
81. Schilsky, M.L. Wilson disease: Current status and the future. Biochimie 2009, 91, 1278–1281.
82. Rashid, S.T.; Corbineau, S.; Hannan, N.; Marciniak, S.J.; Miranda, E.; Alexander, G.; Huang-Doran, I.; Griffin, J.; Ahrlund-Richter, L.; Skepper, J. et al. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J. Clin. Investig. 2010, 120, 3127–3136.
83. Zhang, S.Q.; Chen, S.; Li, W.; Guo, X.P.; Zhao, P.; Xu, J.Y.; Chen, Y.; Pan, Q.; Liu, X.R.; Zychlinski, D. et al. Rescue of ATP7B function in hepatocyte-like cells from Wilson’s disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. Hum. Mol. Genet. 2011, 20, 3176–3187.
84. Gupta, S. Cell therapy to remove excess copper in Wilson’s disease. Ann. N. Y. Acad. Sci. 2014, 1315, 70–80.