1. Achila, D., Banci, L., Bertini, I., Bunce, J., Ciofi-Baffoni, S., & Huffman, D. L. (2006). Structure of human Wilson protein domains 5 and 6 and their interplay with domain 4 and the copper chaperone HAH1 in copper uptake. Proceedings of the National Academy of Sciences of the United States of America, 103(15), 5729–5734. https://doi.org/10.1073/pnas.0504472103
MBD 2 and 4 are Cu(I) acceptors from a copper metallochaperone HAH1 which may subsequently interact with MBD 5 and 6 to induce copper translocation. The mechanism by which this occurs is unknown, but it proposes a role for MBD 2 and 4 in copper transport.
2. Ameta, R., K. Chohadia, A., Jain, A., & Punjabi, P. B. (2018). Chapter 3—Fenton and Photo-Fenton Processes. In S. C. Ameta & R. Ameta (Eds.), Advanced Oxidation Processes for Waste Water Treatment (pp. 49–87). Academic Press. https://doi.org/10.1016/B978-0-12-810499-6.00003-6
The Fenton reaction often occurs in the presence of iron, but can also occur with copper.
3. Banci, L., Bertini, I., Cantini, F., Rosenzweig, A. C., & Yatsunyk, L. A. (2008). Metal Binding Domains 3 and 4 of the Wilson Disease Protein: Solution Structure and Interaction with the Copper(I) Chaperone HAH1. Biochemistry, 47(28), 7423–7429. https://doi.org/10.1021/bi8004736
HAH1 interacts selectively with specific MBDs of ATP7B, and it was only able to form stable interactions with MBD 4 (not MBD 3). The roles of the MBDs likely involve the interactions of the MBDs with other MBDs and metallochaperones as well as the rest of the ATPase.
4. Bie, P. de, Muller, P., Wijmenga, C., & Klomp, L. W. J. (2007). Molecular pathogenesis of Wilson and Menkes disease: Correlation of mutations with molecular defects and disease phenotypes. Journal of Medical Genetics, 44(11), 673–688. https://doi.org/10.1136/jmg.2007.052746
Summary and description of various known disease-causing mutations and how certain better understood mutations cause a loss of function in ATP7B.
5. Birben, E., Sahiner, U. M., Sackesen, C., Erzurum, S., & Kalayci, O. (2012). Oxidative Stress and Antioxidant Defense. The World Allergy Organization Journal, 5(1), 9–19. https://doi.org/10.1097/WOX.0b013e3182439613
Breakdown of some of the endogenous sources of ROS and how they can be produced by metals such as iron and copper through the Fenton Reaction. Effects of oxidative stress and various enzymatic and nonenzymatic antioxidants are described.
6. Cooper, A. M., Eckhardt, R. D., Faloon, W. W., & Davidson, C. S. (1950). INVESTIGATION OF THE AMINOACIDURIA IN WILSON’S DISEASE (HEPATOLENTICULAR DEGENERATION): DEMONSTRATION OF A DEFECT IN RENAL FUNCTION. The Journal of Clinical Investigation, 29(3), 265–278. https://doi.org/10.1172/JCI102254
Patients with hepatolenticular degeneration experienced amino acid excretion at considerably higher amounts than healthy individuals.
7. Cousins, R. J. (1985). Absorption, transport, and hepatic metabolism of copper and zinc: Special reference to metallothionein and ceruloplasmin. Physiological Reviews, 65(2), 238–309. https://doi.org/10.1152/physrev.1985.65.2.238
Several different copper binding molecules are discussed in the context of copper circulation. Metallothionein, albumin, free amino acids, and ceruloplasmin are all implicated as copper-carrying molecules.
8. Dening, T. R., & Berrios, G. E. (1989). Wilson’s Disease: Psychiatric Symptoms in 195 Cases. Archives of General Psychiatry, 46(12), 1126–1134. https://doi.org/10.1001/archpsyc.1989.01810120068011
Psychiatric symptoms of several Wilson Disease cases are described and percentage of all cases with specific symptoms is shown.
9. Denny-Brown, D., & Porter, H. (1951). The Effect of BAL (2,3-Dimercaptopropanol) on Hepatolenticular Degeneration (Wilson’s Disease). New England Journal of Medicine, 245(24), 917–925. https://doi.org/10.1056/NEJM195112132452401
The authors present that patients with hepatolenticular degeneration have buildup of copper in the brain, which accounts for the physiological consequences associated with the disease. 2,3-dimercaptopropanol (BAL), a chelating agent, has been shown to promote the excretion of several metals, such as mercury, gold, silver, and copper. Five patients’ conditions improved upon injection of BAL, excreting more copper, and after stopping, symptoms returned.
10. Dmitriev, O., Tsivkovskii, R., Abildgaard, F., Morgan, C. T., Markley, J. L., & Lutsenko, S. (2006). Solution structure of the N-domain of Wilson disease protein: Distinct nucleotide-binding environment and effects of disease mutations. Proceedings of the National Academy of Sciences of the United States of America, 103(14), 5302–5307. https://doi.org/10.1073/pnas.0507416103
Considers the functional defects of certain N-domain mutations. Predicts that H1069Q reduces tight-binding of ATP at the conserved nucleotide binding domain, which suggests a way in which this common mutation causes a loss of function in the transporter.
11. Flora, S. J. S., & Pachauri, V. (2010). Chelation in Metal Intoxication. International Journal of Environmental Research and Public Health, 7(7), 2745–2788. https://doi.org/10.3390/ijerph7072745
Describes chelating compounds and the chemistry behind their function in binding metals. Pharmacologic profiles and structures of various commonly used chelating compounds are included.
12. Frommer, D. J. (1974). Defective biliary excretion of copper in Wilson’s disease. Gut, 15(2), 125–129. https://doi.org/10.1136/gut.15.2.125
Copper concentration in bile was reduced in WD patients despite a similar rate of bile excretion. Individuals with other liver diseases did not show the same lowered copper concentration in bile. The author proposes that the inability to secrete copper in the bile from lysosomes and tissues may be the result of an ineffective copper-transporting enzyme and diminished binding of copper to ceruloplasmin.
13. Frydman, M. (1990). Genetic aspects of Wilson’s disease. Journal of Gastroenterology and Hepatology, 5(4), 483–490. https://doi.org/10.1111/j.1440-1746.1990.tb01427.x
The disease has an autosomal recessive mode of inheritance, and the HLD gene locus is likely to be on chromosome 13 linked to the ESD gene, which is responsible for an enzyme in erythrocytes. There is a high chance that across various families that have WD that WD is caused by a mutation at a single region of chromosome 13.
14. Gaetke, L. M., Chow-Johnson, H. S., & Chow, C. K. (2014). Copper: Toxicological relevance and mechanisms. Archives of Toxicology, 88(11), 1929–1938. https://doi.org/10.1007/s00204-014-1355-y
Mechanisms of copper toxicity are described, such as oxidative damage, gene expression, and altered interactions with proteins and lipids.
15. Goldfischer, S., Popper, H., & Sternlieb, I. (1980). The significance of variations in the distribution of copper in liver disease. The American Journal of Pathology, 99(3), 715–730.
Copper contained in lysosomes appears to be nontoxic, whereas cytoplasmic copper appears to be cytotoxic. This cytotoxic diffuse copper may be responsible for WD symptoms.
16. González-Guerrero, M., & Argüello, J. M. (2008). Mechanism of Cu+-transporting ATPases: Soluble Cu+ chaperones directly transfer Cu+ to transmembrane transport sites. Proceedings of the National Academy of Sciences, 105(16), 5992–5997. https://doi.org/10.1073/pnas.0711446105
Functions of ATPases and their domains in transporting Cu(I) across membranes. Domain architecture and ATPase structure is discussed.
17. Guttmann, S., Bernick, F., Naorniakowska, M., Michgehl, U., Groba, S. R., Socha, P., Zibert, A., & Schmidt, H. H. (2018). Functional Characterization of Novel ATP7B Variants for Diagnosis of Wilson Disease. Frontiers in Pediatrics, 6. https://doi.org/10.3389/fped.2018.00106
The authors discuss a novel mutation, L168P, in a young patient who presents with neurological symptoms. They consider future work in identifying genetic mutations early so that timely diagnosis and treatment can be given, as pediatric diagnosis is especially difficult in Wilson Disease.
18. Halliwell, B., & Gutteridge, J. M. C. (2015). Free Radicals in Biology and Medicine. Oxford University Press.
The effects of free radicals in biological systems.
19. Harris, E. D. (2000). Cellular Copper Transport and Metabolism. Annual Review of Nutrition, 20(1), 291–310. https://doi.org/10.1146/annurev.nutr.20.1.291
Breakdown of various cellular copper transport tools. Albumin and ceruloplasmin binding sites are discussed with reference to binding residues.
20. Harry, J., & Tripathi, R. (1970). Kayser-Fleischer ring. A pathological study. The British Journal of Ophthalmology, 54(12), 794–800.
Physical characteristics and ultrastructural alterations associated with the Kayser-Fleischer ring. Various images of electron density throughout corneal fragments are shown and discussed in the context of metal deposition.
21. Hoogenraad, T. U., Koevoet, R., & Korver, E. G. W. M. de R. (1979). Oral Zinc Sulphate as Long-Term Treatment in Wilson’s Disease (Hepatolenticular Degeneration). European Neurology, 18(3), 205–211. https://doi.org/10.1159/000115077
The authors consider zinc supplementation as a viable means of reducing copper accumulation in Wilson Disease patients. Zinc is less toxic than other chelating agents and may be able to reduce accumulated copper while also preventing accumulation to begin with. This leads zinc to be a potential long term treatment of Wilson Disease.
22. Hoogenraad, Tjaard Ubbo. (2006). Paradigm shift in treatment of Wilson’s disease: Zinc therapy now treatment of choice. Brain and Development, 28(3), 141–146. https://doi.org/10.1016/j.braindev.2005.08.008
Oral zinc sulphate has emerged as one of the most popular means of treating Wilson Disease because of its low toxicity and effectiveness in inducing metallothionein, a protein with preferential affinity for copper. Upon binding copper (which is more favorable than zinc), the copper is detoxified. Chelating treatments have been shown to be a poor initial treatment due to the potential they have in worsening symptoms.
23. Hung, I. H., Suzuki, M., Yamaguchi, Y., Yuan, D. S., Klausner, R. D., & Gitlin, J. D. (1997). Biochemical Characterization of the Wilson Disease Protein and Functional Expression in the Yeast Saccharomyces cerevisiae. Journal of Biological Chemistry, 272(34), 21461–21466. https://doi.org/10.1074/jbc.272.34.21461
A large portion of ATP7B is localized to the TGN. Copper-induced relocalization of ATP7B was seen when cells were incubated in 200 uM copper. Application of copper chelating agents yielded a return of ATP7B to the TGN.
24. Husak, V. (2015). COPPER AND COPPER-CONTAINING PESTICIDES: METABOLISM, TOXICITY AND OXIDATIVE STRESS. Journal of Vasyl Stefanyk Precarpathian National University, 2. https://doi.org/10.15330/jpnu.2.1.38-50
Breakdown of copper homeostasis in hepatic cells and copper metabolism in the body. There are many helpful images in the document that illustrate the movement of copper throughout cells and systems. Copper toxicity threshhold in humans is around 11 mg/kg. An image of the Haber-Weiss and Fenton Reactions from this source is used.
25. Huster, D., Hoppert, M., Lutsenko, S., Zinke, J., Lehmann, C., Mössner, J., Berr, F., & Caca, K. (2003). Defective cellular localization of mutant ATP7B in Wilson’s disease patients and hepatoma cell lines. Gastroenterology, 124(2), 335–345. https://doi.org/10.1053/gast.2003.50066
The authors utilize electron microscopy and ATP7B-GFP fusion proteins to show cellular localization of ATP7B. They find that many disease-causing mutations of ATP7B result in mislocalization of ATP7B and may explain the cause of copper accumulation in Wilson Disease. There method can be adapted for future work in deetermining the effects of novel missense mutations in ATP7B.
26. KALER, S. G. (2013). Inborn errors of copper metabolism. Handbook of Clinical Neurology, 113, 1745–1754. https://doi.org/10.1016/B978-0-444-59565-2.00045-9
A review of various diseases that cause errors in copper metabolism, including Wilson Disease. The possibility of gene therapy as a future treatment for Wilson Disease is considered, and various treatments and physical symptoms of the disease are explained. Differences in clinical manifestations are discussed, including the more common presentation of KF rings in patients with neurological symptoms (95% as opposed to 65% of patients presenting with liver disease symptoms).
27. Kusuda, Y., Hamaguchi, K., Mori, T., Shin, R., Seike, M., & Sakata, T. (2000). Novel mutations of the ATP7B gene in Japanese patients with Wilson disease. Journal of Human Genetics, 45(2), 86–91. https://doi.org/10.1007/s100380050017
The authors discuss 2 novel mutations in the ATP7B gene among others that cause WD. Mutations that cause WD include a deletion, which causes a truncated protein seen in some WD patients or a disruption of the ATP hinge region, and missense mutations. They discuss 16 polymorphisms. The authors aim to investigate phenotype-genotype relationships in the future as well as population-specific mutations, as their studies showed different mutations across populations.
28. Litwin, T., Dzieżyc, K., Karliński, M., Chabik, G., Czepiel, W., & Członkowska, A. (2015). Early neurological worsening in patients with Wilson’s disease. Journal of the Neurological Sciences, 355(1), 162–167. https://doi.org/10.1016/j.jns.2015.06.010
The authors find that after initial treatment with de-coppering drugs, 11% of patients exhibited a worsening of neurological symptoms. In most cases the worsening was reversible.
29. Lönnerdal, B. (1996). Bioavailability of copper. The American Journal of Clinical Nutrition, 63(5), 821S-829S. https://doi.org/10.1093/ajcn/63.5.821
A review of the common sources of copper intake with relative copper concentrations of various types of foods. Copper is highly concentrated in beef liver, shellfish, nuts, and seeds.
30. Luedde, T., Kaplowitz, N., & Schwabe, R. F. (2014). Cell Death and Cell Death Responses in Liver Disease: Mechanisms and Clinical Relevance. Gastroenterology, 147(4), 765-783.e4. https://doi.org/10.1053/j.gastro.2014.07.018
Hepatic cell death is highly regulated, though nearly all liver diseases are associated with hepatic cell death. Liver fibrosis is caused by massive hepatic cell damage and cell death.
31. Lutsenko, S. (2016). Copper trafficking to the secretory pathway. Metallomics : Integrated Biometal Science, 8(9), 840–852. https://doi.org/10.1039/c6mt00176a
Cytosolic metallochaperone ATOX-1 interacts with the MBDs of ATP7A and ATP7B. ATOX-1 binds copper with a Kd of 2.1(2) × 10−18–6.3 × 10−19 M. The copper binding site of ATOX-1 consists of C-G-G-C.
32. Lutsenko, S., Barnes, N. L., Bartee, M. Y., & Dmitriev, O. Y. (2007). Function and Regulation of Human Copper-Transporting ATPases. Physiological Reviews, 87(3), 1011–1046. https://doi.org/10.1152/physrev.00004.2006200
A review of copper metabolism and copper transporter ATPases. Copper distribution throughout the body and mechanisms by which it is excreted ot circulated.
33. Mufti, A. R., Burstein, E., Csomos, R. A., Graf, P. C. F., Wilkinson, J. C., Dick, R. D., Challa, M., Son, J.-K., Bratton, S. B., Su, G. L., Brewer, G. J., Jakob, U., & Duckett, C. S. (2006). XIAP Is a Copper Binding Protein Deregulated in Wilson’s Disease and Other Copper Toxicosis Disorders. Molecular Cell, 21(6), 775–785. https://doi.org/10.1016/j.molcel.2006.01.033
X-linked inhibitor of apoptosis (XIAP) is a cell death regulatory protein that is reduced in WD patients. XIAP irreversibly binds copper especially when copper is in excess, inhibiting its normal function of inhibiting caspase-3. This causes less regulation of apoptosis, leading to more cell death and implicating XIAP as an important protein in copper-related illnesses.
34. Mylonas, C., & Kouretas, D. (1999). Lipid peroxidation and tissue damage. In Vivo (Athens, Greece), 13(3), 295–309.
Lipid peroxidation and the mechanism by which it drives tissue damage. Many diseases, including Parkinson’s disease (which presents with similar neurological symptoms to WD), have been associated with lipid peroxidation. Lipid peroxidation is self-propogating, which makes widespread tissue damage possible even with very little initial oxidative damage to membrane lipids.
35. Nagasaka, H., Inoue, I., Inui, A., Komatsu, H., Sogo, T., Murayama, K., Murakami, T., Yorifuji, T., Asayama, K., Katayama, S., Uemoto, S., Kobayashi, K., Takayanagi, M., Fujisawa, T., & Tsukahara, H. (2006). Relationship Between Oxidative Stress and Antioxidant Systems in the Liver of Patients With Wilson Disease: Hepatic Manifestation in Wilson Disease as a Consequence of Augmented Oxidative Stress. Pediatric Research, 60(4), 472–477. https://doi.org/10.1203/01.pdr.0000238341.12229.d3
Lipid peroxidation product TBARS is found to be substantially higher in Wilson Disease patients. GSH:GSSG ratio was also lowered in Wilson Disease patients, which typically indicates oxidative stress.
36. Oder, W., Grimm, G., Kollegger, H., Ferenci, P., Schneider, B., & Deecke, L. (1991). Neurological and neuropsychiatric spectrum of Wilson’s disease: A prospective study of 45 cases. Journal of Neurology, 238(5), 281–287. https://doi.org/10.1007/BF00319740
There is large variability in neurological symptoms associated with Wilson Disease. Tremors are a common symptom, with over 39% of patients in the study experiencing them. Dysarthria was very common even in long-term treated patients.
37. Ogihara, H., Ogihara, T., Miki, M., Yasuda, H., & Mino, M. (1995). Plasma Copper and Antioxidant Status in Wilson’s Disease. Pediatric Research, 37(2), 219–226. https://doi.org/10.1203/00006450-199502000-00016
Chelating treatments helped restore antioxidant concentrations in Wilson Disease patients. Testing blood for antioxidants may be an effective way of monitoring disease progression.
38. Parisi, S., Polishchuk, E. V., Allocca, S., Ciano, M., Musto, A., Gallo, M., Perone, L., Ranucci, G., Iorio, R., Polishchuk, R. S., & Bonatti, S. (2018). Characterization of the most frequent ATP7B mutation causing Wilson disease in hepatocytes from patient induced pluripotent stem cells. Scientific Reports, 8. https://doi.org/10.1038/s41598-018-24717-0
The H1069Q mutant is severely mislocalized to the ER, as evidenced by immuno-electron microscopy. An image from this used to illustrated H1069Q mislocalization in the cell. Trafficking of the H1069Q mutant is also very impaired.
39. Polishchuk, E. V., Concilli, M., Iacobacci, S., Chesi, G., Pastore, N., Piccolo, P., Paladino, S., Baldantoni, D., van IJzendoorn, S. C. D., Chan, J., Chang, C. J., Amoresano, A., Pane, F., Pucci, P., Tarallo, A., Parenti, G., Brunetti-Pierri, N., Settembre, C., Ballabio, A., & Polishchuk, R. S. (2014). Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis. Developmental Cell, 29(6), 686–700. https://doi.org/10.1016/j.devcel.2014.04.033
ATP7B relocalizes in response to high intracellular copper concentrations, and is found to deliver copper to lysosomes which assist in copper excretion.
40. Polishchuk, R., & Lutsenko, S. (2013). GOLGI IN COPPER HOMEOSTASIS: A VIEW FROM THE MEMBRANE TRAFFICKING FIELD. Histochemistry and Cell Biology, 140(3), 285–295. https://doi.org/10.1007/s00418-013-1123-8
The TGN is essential for copper homeostasis as it is the site of ceruloplasmin loading. Ceruloplasmin is the most abundant copper carrying protein in the blood and plays a major role in circulation of copper to body tissues. ATP7B is trafficked from the TGN in response to high copper concentrations, and ceruloplasmin is released from the TGN for copper circulation.
41. Roberts, E. A., & Sarkar, B. (2008). Liver as a key organ in the supply, storage, and excretion of copper. The American Journal of Clinical Nutrition, 88(3), 851S-854S. https://doi.org/10.1093/ajcn/88.3.851S
A review of liver function in maintaining copper homeostasis with information about daily copper intake and common foods that have copper. Roles of copper in cells include SOD1 and cytochrome c oxidase.
42. Roberts, E. A., & Schilsky, M. L. (2008). Diagnosis and treatment of Wilson disease: An update. Hepatology, 47(6), 2089–2111. https://doi.org/10.1002/hep.22261
Relays steps for determining a Wilson Disease diagnosis. The KF ring leads to an immediate diagnosis in patients presenting with liver disease. The most accurate way to diagnose Wilson Disease is through genetic testing, and when results are for whatever reason inconclusive, urinary copper concentration can be used as an indicator of Wilson Disease.
43. Ruttkay-Nedecky, B., Nejdl, L., Gumulec, J., Zitka, O., Masarik, M., Eckschlager, T., Stiborova, M., Adam, V., & Kizek, R. (2013). The Role of Metallothionein in Oxidative Stress. International Journal of Molecular Sciences, 14(3), 6044–6066. https://doi.org/10.3390/ijms14036044
Metallothioneins are heavily involved in protecting cells from oxidative stress. They can bind and detoxify oxidants and electrophiles, as well as metals, that can all cause oxidative damage.
44. Sass-Kortsak, A., Cherniak, M., Geiger, D. W., & Slater, R. J. (1959). OBSERVATIONS ON CERULOPLASMIN IN WILSON’S DISEASE*. Journal of Clinical Investigation, 38(10 Pt 1-2), 1672–1682.
Low ceruloplasmin levels were not seen in a patient who clearly had Wilson’s Disease, casting doubt on the credibility of using low ceruloplasmin levels as a way to diagnose the disease. Increasing ceruloplasmin levels in patients with Wilson’s disease has failed to reduce symptoms. There is a significant delay in copper incorporation into ceruloplasmin in Wilson’s disease patients, which could potentially be caused by a considerably expanded copper pool in these patients, diluting the signal-producing Cu64.
45. Scheinberg, I. H., & Gitlin, D. (1952). Deficiency of Ceruloplasmin in Patients with Hepatolenticular Degeneration (Wilson’s Disease). Science, 116(3018), 484–485. JSTOR.
Individuals with Wilson’s Disease have a lower serum ceruloplasmin level than normal. Ceruloplasmin binds copper and carries it through the blood. This paper makes a connection between hepatolenticular degeneration, copper, and ceruloplasmin, which plays a pivotal role in copper metabolism.
46. Scheinberg, I. H., & Morell, A. G. (1957). Exchange of Ceruloplasmin Copper With Ionic CU64 With Reference to Wilson’s Disease1. Journal of Clinical Investigation, 36(8), 1193–1201.
Half of the maximum copper bound to ceruloplasmin (4 atoms) can exchange for free copper, showing that copper can be reversibly released from ceruloplasmin. Copper released from ceruloplasmin may also be able to diffuse across semi-permeable membranes, and a lack of ceruloplasmin leads to a lack of diffusible copper, leading to copper deposition in tissue.
47. Schilsky, M. L., Blank, R. R., Czaja, M. J., Zern, M. A., Scheinberg, I. H., Stockert, R. J., & Sternlieb, I. (1989). Hepatocellular copper toxicity and its attenuation by zinc. Journal of Clinical Investigation, 84(5), 1562–1568.
Zinc has a protective effect on copper toxicity, where cells incubated with copper and zinc received less damage cells without zinc. This occurs through the induction of metallothionein which can bind and detoxify copper. Zinc may also have direct action on hepatocytes in addition to enterocytes, where they are known to induce metallothionein.
48. Smirnova, J., Kabin, E., Järving, I., Bragina, O., Tõugu, V., Plitz, T., & Palumaa, P. (2018). Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent. Scientific Reports, 8(1), 1–9. https://doi.org/10.1038/s41598-018-19873-2
The number of sulfur atoms in copper binding/chelating drugs appears to correlate with the effectiveness of binding. Increasing distance between sulfhydryl groups appears to decrease the effectiveness of binding. Alpha-lipoic acid may protect hepatic cells from copper toxicity, as demonstrated through cell cultures. Further investigation of lipoic acid may implicate the compound as an effective treatment for WD as it may reduce copper toxicity in hepatic cells.
49. Sokol, R. J., Twedt, D., McKim, J. M., Devereaux, M. W., Karrer, F. M., Kam, I., Von Steigman, G., Narkewicz, M. R., Bacon, B. R., Britton, R. S., & Neuschwander-Tetri, B. A. (1994). Oxidant injury to hepatic mitochondria in patients with Wilson’s disease and Bedlington terriers with copper toxicosis. Gastroenterology, 107(6), 1788–1798. https://doi.org/10.1016/0016-5085(94)90822-2
Membrane-bound alpha-tocopherol, a type of vitamin E, is decreased in Wilson Disease patients consistent with oxidative stress. The rise in TBARS is characteristic of a more advanced disease state, lending evidence to the idea that oxidative damage is present in advanced liver damage.
50. Stern, B. R., Solioz, M., Krewski, D., Aggett, P., Aw, T.-C., Baker, S., Crump, K., Dourson, M., Haber, L., Hertzberg, R., Keen, C., Meek, B., Rudenko, L., Schoeny, R., Slob, W., & Starr, T. (2007). Copper and Human Health: Biochemistry, Genetics, and Strategies for Modeling Dose-response Relationships. Journal of Toxicology and Environmental Health, Part B, 10(3), 157–222. https://doi.org/10.1080/10937400600755911
Copper is absorbed in the intestine where it travels through portal blood attached to albumin, gluthathione, or amino acids. It is then taken up primarily in the liver. It is primarily excreted in bile, and 72% of radioactive copper consumed by healthy individuals was excreted in waste.
51. Sternlieb, I., Hamer, C. J. A. van den, Morell, A. G., Alpert, S., Gregoriadis, G., & Scheinberg, I. H. (1973). Lysosomal Defect of Hepatic Copper Excretion in Wilson’s Disease (Hepatolenticular Degeneration). Gastroenterology, 64(1), 99–105. https://doi.org/10.1016/S0016-5085(73)80096-4
Copper concentration in the bile of Wilson’s disease patients was significantly lower than normal, indicating poor biliary excretion of copper. In patients with advanced WD, there is an increased concentration of lysosomal copper, suggesting a lysosomal defect driven by an inability to excrete copper into the bile. This may lead to future research in WD as a lysosome associated disease.
52. Tanzi, R. E., Petrukhin, K., Chernov, I., Pellequer, J. L., Wasco, W., Ross, B., Romano, D. M., Parano, E., Pavone, L., Brzustowicz, L. M., Devoto, M., Peppercorn, J., Bush, A. I., Sternlieb, I., Pirastu, M., Gusella, J. F., Evgrafov, O., Penchaszadeh, G. K., Honig, B., … Gilliam, T. C. (1993). The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nature Genetics, 5(4), 344–350. https://doi.org/10.1038/ng1293-344
WD is caused by a loss of function mutation in a copper transporting ATPase, which is consistent with the phenotypes of the disease. The gene product is very similar to the protein associated with Menkes Disease, which is also associated with defective copper transport. The protein likely resides in membranes responsible for copper excretion into bile, consistent with previous work detailing the lack of sufficient copper concentration in bile. It is still unknown why the ceruloplasmin deficiency/ineffectiveness seen in WD patients.
53. Terada, K., Schilsky, M. L., Miura, N., & Sugiyama, T. (1998). ATP7B (WND) protein. The International Journal of Biochemistry & Cell Biology, 30(10), 1063–1067. https://doi.org/10.1016/S1357-2725(98)00073-9
ATP7B gene contains 21 exons encoding a protein of 1465 amino acids. Splice variants have been found in the brain, kidneys, and placenta, and ATP7B is commonly expressed in the liver, brain, and kidneys. The structural features of the protein include an N-domain, a P-domain, and an A-domain, all of which have highly conserved motifs and are essential to its function in transporting Cu(I). There are 6 MBDs on the N-terminal end of the protein.
54. Uauy, R., Olivares, M., & Gonzalez, M. (1998). Essentiality of copper in humans. The American Journal of Clinical Nutrition, 67(5), 952S-959S. https://doi.org/10.1093/ajcn/67.5.952S
Copper is essential for Cox activity, as it catalyzes the reduction of molecular oxygen to water and maintains a proton gradient for respiration. It is also an important cofactor in certain transcription factors, such as ACE1. Pregnancy is associated with high copper retention, which reflects the importance of copper in developing fetuses that can only receive maternal copper.
55. van de Sluis, B. (2019). Chapter 7—COMMD1 in Copper Homeostasis. In N. Kerkar & E. A. Roberts (Eds.), Clinical and Translational Perspectives on WILSON DISEASE (pp. 57–63). Academic Press. https://doi.org/10.1016/B978-0-12-810532-0.00007-0
COMMD1 interacts with ATP7B and is involved in trafficking of ATP7B. COMMD1 is believed to be involved specifically in copper excretion with lysosomes.
56. Walshe, J. M. (1956). Penicillamine, a new oral therapy for Wilson’s disease. The American Journal of Medicine, 21(4), 487–495. https://doi.org/10.1016/0002-9343(56)90066-3
BAL has been shown to work mostly in people who have severe forms of the disease, but has been seen to also have negative side effects in some patients. Penicillamine is an oral drug that causes more copper to be excreted in the urine. It is not necessarily more effective than BAL, but no immediate toxic side-effects have been seen as a result of penicillamine intake.
57. Wilson, S. a. K. (1912). PROGRESSIVE LENTICULAR DEGENERATION: A FAMILIAL NERVOUS DISEASE ASSOCIATED WITH CIRRHOSIS OF THE LIVER. Brain, 34(4), 295–507. https://doi.org/10.1093/brain/34.4.295
Wilson describes a rare novel disease which he calls “Progressive Lenticular Degeneration” which is characterized by nervous symptoms such as involuntary movement as well as liver cirrhosis. The disease is familial and is often fatal.
58. Wilson, S. A. K. (1934). Kayser-Fleischer Ring in Cornea in two Cases of Wilson’s Disease (Progressive Lenticular Degeneration). Proceedings of the Royal Society of Medicine, 27(3), 297–298.
The Kayser-Fleisher ring is described as a consequence of an undetermined form of liver cirrhosis. Patients with the ring had nervous symptoms associated with lenticular degeneration. It is believed that the liver disorder preceded the nervous symptoms.
59. Wu, F., Wang, J., Pu, C., Qiao, L., & Jiang, C. (2015). Wilson’s Disease: A Comprehensive Review of the Molecular Mechanisms. International Journal of Molecular Sciences, 16(3), 6419–6431. https://doi.org/10.3390/ijms16036419
Over 300 disease-causing mutations have been identified in ATP7B. There are a wide variety of mutations and their prevelance among populations is regional. H1069Q is most common among Caucasian populations, and R778L is more common in East Asia. The variability in disease-causing mutations can make diagnosis difficult.
60. Yoshida, K., Furihata, K., Takeda, S., Nakamura, A., Yamamoto, K., Morita, H., Hiyamuta, S., Ikeda, S., Shimizu, N., & Yanagisawa, N. (1995). A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nature Genetics, 9(3), 267–272. https://doi.org/10.1038/ng0395-267
A genetic defect in ceruloplasmin can cause hemosiderosis, the toxic accumulation of iron in various tissues. This is interesting in the context of Wilson Disease, where you would expect to see an increase in copper concentration in many tissues, though this report indicates that there was larger iron concentration in tissues. This also has implications for the role of ceruloplasmin in binding other metals, such as iron.
61. Yu, C. H., Lee, W., Nokhrin, S., & Dmitriev, O. Y. (2018). The Structure of Metal Binding Domain 1 of the Copper Transporter ATP7B Reveals Mechanism of a Singular Wilson Disease Mutation. Scientific Reports, 8(1), 1–6. https://doi.org/10.1038/s41598-017-18951-1
MBD 1-4 of ATP7B likely have a regulatory role, and mutations in these areas are among the least common disease-causing mutations. MBD5 and 6 are more proximal to the membrane and mutations in these MBDs are more commonly associated with Wilson Disease. G85V in MBD1 causes a misfolding of MBD1, which disrupts its interactions with MBD2 and 3, which may also lead to degradation of the misfolded protein.
62. Zischka, H., & Einer, C. (2018). Mitochondrial copper homeostasis and its derailment in Wilson disease. The International Journal of Biochemistry & Cell Biology, 102, 71–75. https://doi.org/10.1016/j.biocel.2018.07.001
Copper accumulates in the mitochondrial membranes causing deformation of the structure as well as dilation of the cristae. This reduces the overall efficiency of the mitochondria. These ultrastructural alterations are believed to precede extensive oxidative damage.
63. Zischka, H., Lichtmannegger, J., Schmitt, S., Jägemann, N., Schulz, S., Wartini, D., Jennen, L., Rust, C., Larochette, N., Galluzzi, L., Chajes, V., Bandow, N., Gilles, V. S., DiSpirito, A. A., Esposito, I., Goettlicher, M., Summer, K. H., & Kroemer, G. (2011). Liver mitochondrial membrane crosslinking and destruction in a rat model of Wilson disease. The Journal of Clinical Investigation, 121(4), 1508–1518. https://doi.org/10.1172/JCI45401
Mitochondria become overloaded by copper long before evidence of oxidative damage is seen in the cell. Structural damage from the accumulation of this copper in mitochondria occurred before symptoms presented, and the functions of the mitochondria are severely impaired. Only in late-stage disease is there evidence of oxidative damage and mitochondrial destruction.
