Molecular Genetics of Wilson Disease

Eve A Roberts, University of Toronto, Toronto, Ontario, Canada

Published online: April 2013

DOI: 10.1002/9780470015902.a0024373

Wilson disease is an autosomal-recessive genetic disorder of hepatocellular copper disposition. It is rare but has a worldwide distribution. It is clinically diverse. Disease patterns include various kinds of liver disease; neurological movement disorders and psychiatric disease including psychosis, and less commonly recurrent haemolytic anaemia, osseomuscular abnormalities and cardiac dysrhythmias. The classic eye finding, the Kayser–Fleischer ring, has no functional impact. Thus far, only one gene has been identified whose mutations are causal for Wilson disease, ATP7B on chromosome 13q14.3, cloned in 1993. More than 500 mutations have been identified. The encoded protein is a metal-transporting P-type adenosine triphosphatase (ATPase), the Wilson ATPase, similar to copper transporters across the phyla. Simple genotypic explanation for the phenotypic diversity does not exist. The important genotype–phenotype correlation is that if the Wilson ATPase is absent or nonfunctional, severe disease (usually hepatic) commonly develops in the first decade of life. Clinically evident Wilson disease is fatal if not treated. The broad age range of diagnoses (3–80+ years) raises the question of incomplete penetrance, an issue along with gene modifiers currently under investigation. The possibility that mutations in other genes may result in Wilson disease has not been entirely eliminated. The contribution of ATP7B to non-Wilsonian diseases is being determined.

Key Concepts:

  • Wilson disease is a rare (30 per million population, on average) autosomal-recessive disorder of hepatic copper disposition.
  • Wilson disease can present as almost any form of hepatic disease, or as neurological movement disorders, or as psychiatric disease.
  • Genetic diagnosis is definitive; clinical application of genetic findings requires skilled interpretation; success rate for identifying one or both mutations can be highly variable. Most affected individuals are compound heterozygotes. Genetic testing is most efficient for investigating first-degree relatives, who must be assessed for Wilson disease once a single family member has been diagnosed with Wilson disease.
  • Wilson disease is an example of ‘endogenous hepatotoxicity’ where a normal component of the functioning organism is mishandled and becomes toxic. The mechanism of liver (and likely brain) damage involves oxidative stress with damage to mitochondria; apoptosis is typical. Concepts relating to drug-induced hepatotoxicity are highly relevant to understanding the mechanism of damage and devising treatments. Metalloproteomics is a research strategy for examining copper disposition in normal and abnormal models/organisms.
  • More than 500 mutations in ATP7B have been identified. These are mainly missense mutations, and less frequently small deletions or insertions, nonsense or splice-site mutations. In contrast, the homologous gene ATP7A, abnormal in the X-linked recessive disorder Menkes disease (with copper insufficiency), displays mainly large deletions.
  • Predictably, the phenotypic variation depends on complex factors besides the genotype. The only important genotype–phenotype correlation is that severe disease (usually hepatic) typically develops very early in life if the Wilson ATPase is absent or nonfunctional. A convincing example of this correlation is provided by comparison of the Atp7b-knockout mouse and the toxic milk (tx-j) mouse, which has a point mutation.
  • Few modifying genes have been identified. Candidates include apolipoprotein E, human prion gene and BIRC4/XIAP. Females seem to have more severe Wilson disease.
  • Other disorders of copper disposition exist. These include defects in ceruloplasmin production (aceruloplasminaemia and AT-1 defect), various congenital glycosylation disorders, Indian childhood cirrhosis and its variants. In the Bedlington terrier, hepatic copper toxicosis is usually related to mutations in the gene for COMMD1.
  • ATP7B may play a secondary role in some forms of Alzheimer disease. The Wilson ATPase plays a direct role in the hepatocellular handling of platinum compounds such as cisplatin.

Keywords: Wilson disease; hepatolenticular degeneration; copper; ATP7B; Wilson ATPase; reactive oxygen species; oxidative stress; metalloproteomics

Figure 1. Wilson disease as endogenous hepatotoxicity. Copper mishandled, because of ATP7B mutation, accumulates and becomes hepatotoxic. Other metabolic disorders also fit the description of ‘endogenous hepatotoxicity’ including diseases where other normal chemicals are mishandled (e.g. hereditary fructose intolerance and hereditary tyrosinemia type 1 due to fumarylacetoacetate hydrolase deficiency), or an abnormal protein is produced (e.g. polymerised 1-antitrypsin with PiZ disease). The advantage of regarding these metabolic disorders as endogenous hepatotoxicity is that disease mechanisms and genetic considerations may be similar to those with drug- or toxin-induced liver damage. Adapted from Roberts and Sarkar (2008). © American Society for Nutrition.
Figure 2. Cartoon depicting the Wilson ATPase. The protein has a distinctive copper-binding domain with six copper-binding units featuring a ‘CXXC’ motif towards the amino end. Eight transmembrane segments form a pore: transmembrane segments 6–8 display characteristic motifs involved in transfer of metal. Functional ‘loops’ include an actuator domain and the nucleotide-binding and phosphorylation domains, which provide energy to power to transfer of copper across the membrane. Targeting sequences towards the amino end (AFDNVGYE) and in the short carboxy tail (LLL) support intracellular translocation.
Figure 3. Uptake, intracellular disposition and excretion of copper in a hepatocyte. A doublet of hepatocytes is shown, with the specialised bile canalicular membrane located between two tight junctions (pointed octagons). Copper (Cu; small red circle) is taken up by the sinusoidal plasma membrane, deployed within the hepatocyte by metallochaperones, used in ceruloplasmin production, stored or detoxified, or excreted into bile. The uptake mechanism involves a reductase (cross) and CTR1 (square). Metallochaperones target copper to specific sites: ATOX1 (square) to Wilson ATPase (oval with directional arrow) in trans-Golgi network; Cox17 (green ellipse) to mitochondria; CCS (blue ellipse) to SOD1 in cytoplasm. Glutathione (GSH; blue horseshoe) mediates other intracellular transfer including incorporation into metallothionein (studded stars). When intracellular copper concentrations are low or normal, the Wilson ATPase participates in production of holoceruloplasmin (inverted trapezoid containing copper) in the Golgi apparatus; holoceruloplasmin is then secreted into the blood. When intracellular copper concentrations are elevated, the Wilson ATPase expedites biliary excretion of copper by a process that may also involve COMMD1. Biliary copper excretion can also take place by the transporter MRP2. Adapted from Roberts and Sarkar (2008). © American Society for Nutrition.
Figure 4. Proposed Wilson ATPase interactome. Various proteins interact with the Wilson ATPase, ATP7B. Some of these proteins, but not all, also interact with the Menkes ATPase, ATP7A. Site of interaction with the Wilson ATPase varies (blue square: N-terminal region; red circle: C-terminal region). The status of interaction with the Niemann–Pick protein C1 remains undetermined. As indicated by yellow circles, some interactions have functional utility; purple circles indicate quality-control functions. Adapted from Roberts (2012) based on de Bie et al. (2007). © RSC Publishing.
Figure 5. Cartoon showing distribution of mutations across the ATP7B gene. Most mutations are in exons 8–18, notably as shown by data from European/North American (1997 data representative: filled symbols) and East Asian (Chinese data representative: open symbols) studies. In contrast, in addition to mutations in these mutations, Indian patients show numerous mutations in exons 2–8, perhaps contributing to more severe clinical disease. Abbreviation: trans-memb: transmembrane. Adapted from Shah et al. (1997) with additional data as indicated from Wu et al. (2001), and Gupta et al. (2005). © Elsevier.
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 References
    Barada K, El-Atrache M, El-Hajj II et al. (2010) Homozygous mutations in the conserved ATP hinge region of the Wilson disease gene: association with liver disease. Journal of Clinical Gastroenterology 44(6): 432–439.
    Barada K, Nemer G, El-Hajj II et al. (2007) Early and severe liver disease associated with homozygosity for an exon 7 mutation, G691R, in Wilson's disease. Clinical Genetics 72(3): 264–267.
    Bearn AG, Yu TF and Gutman AB (1957) Renal function in Wilson's disease. Journal of Clinical Investigation 36(7): 1107–1114.
    Bennett J and Hahn SH (2011) Clinical molecular diagnosis of Wilson disease. Seminars in Liver Disease 31(3): 233–238.
    de Bie P, Muller P, Wijmenga C and Klomp LW (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.
    Borjigin J, Payne AS, Deng J et al. (1999) A novel pineal night-specific ATPase encoded by the Wilson disease gene. Journal of Neuroscience 19(3): 1018–1026.
    Bull PC, Thomas GR, Rommens JM, Forbes JR and Cox DW (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genetics 5(4): 327–337.
    Czlonkowska A, Gromadzka G and Chabik G (2009) Monozygotic female twins discordant for phenotype of Wilson's disease. Movement Disorders 24(7): 1066–1069.
    Deguti MM, Genschel J, Cancado EL et al. (2004) Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Human Mutation 23(4): 398.
    Dmitriev O, Tsivkovskii R, Abildgaard F et al. (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 USA 103(14): 5302–5307.
    Dolgova NV, Olson D, Lutsenko S and Dmitriev OY (2009) The soluble metal-binding domain of the copper transporter ATP7B binds and detoxifies cisplatin. Biochemical Journal 419(1): 51–56.
    Fatemi N, Korzhnev DM, Velyvis A, Sarkar B and Forman-Kay JD (2010) NMR characterization of copper-binding domains 4-6 of ATP7B. Biochemistry 49(39): 8468–8477.
    Fatemi N and Sarkar B (2002) Structural and functional insights of Wilson disease copper-transporting ATPase. Journal of Bioenergetics and Biomembrane 34(5): 339–349.
    Fieten H, Leegwater PA, Watson AL and Rothuizen J (2012) Canine models of copper toxicosis for understanding mammalian copper metabolism. Mammalian Genome 23(1–2): 62–75.
    Firneisz G, Szonyi L, Ferenci P et al. (2004) The other mutation is found: follow-up of an exceptional family with Wilson disease. American Journal of Gastroenterology 99(12): 2504–2505.
    Garcia-Villarreal L, Daniels S, Shaw SH et al. (2000) High prevalence of the very rare Wilson disease gene mutation Leu708Pro in the island of Gran Canaria (Canary Islands, Spain): a genetic and clinical study. Hepatology 32(6): 1329–1336.
    Gupta A, Aikath D, Neogi R et al. (2005) Molecular pathogenesis of Wilson disease: haplotype analysis, detection of prevalent mutations and genotype-phenotype correlation in Indian patients. Human Genetics 118(1): 49–57.
    Gupta A, Bhattacharjee A, Dmitriev OY et al. (2011) Cellular copper levels determine the phenotype of the Arg875 variant of ATP7B/Wilson disease protein. Proceedings of the National Academy of Sciences of the USA 108(13): 5390–5395.
    Homburger F and Kozol HL (1946) Hepatolenticular degeneration. Journal of the American Medical Association 130: 6–14.
    Huppke P, Brendel C, Kalscheuer V et al. (2012) Mutations in SLC33A1 cause a lethal autosomal-recessive disorder with congenital cataracts, hearing loss, and low serum copper and ceruloplasmin. American Journal of Human Genetics 90(1): 61–68.
    Huster D, Finegold MJ, Morgan CT et al. (2006) Consequences of copper accumulation in the livers of the Atp7b-/- (Wilson disease gene) knockout mice. American Journal of Pathology 168(2): 423–434.
    Huster D, Kuhne A, Bhattacharjee A et al. (2012) Diverse functional properties of Wilson disease ATP7B variants. Gastroenterology 142(4): 947–956e945.
    Kalinsky H, Funes A, Zeldin A et al. (1998) Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Human Mutation 11(2): 145–151.
    Kegley KM, Sellers MA, Ferber MJ et al. (2010) Fulminant Wilson's disease requiring liver transplantation in one monozygotic twin despite identical genetic mutation. American Journal of Transplantation 10(5): 1325–1329.
    La Fontaine S and Mercer JF (2007) Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Archieves of Biochemistry and Biophysics 463(2): 149–167.
    Lang PA, Schenck M, Nicolay JP et al. (2007) Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nature Medicine 13(2): 164–170.
    Lirong J, Jianjun J, Hua Z et al. (2009) Hypoceruloplasminemia-related movement disorder without Kayser–Fleischer rings is different from Wilson disease and not involved in ATP7B mutation. European Journal of Neurology 16(10): 1130–1137.
    Litwin T, Gromadzka G and Czlonkowska A (2012) Gender differences in Wilson's disease. Journal of the Neurological Sciences 312(1–2): 31–35.
    Luoma LM, Deeb TM, Macintyre G and Cox DW (2010) Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. Human Mutation 31(5): 569–577.
    Madden JW, Ironside JW, Triger DR and Bradshaw JP (1985) An unusual case of Wilson's disease. Quarterly Journal of Medicine 55(216): 63–73.
    Mandato C, Brive L, Miura Y et al. (2006) Cryptogenic liver disease in four children: a novel congenital disorder of glycosylation. Pediatric Research 59(2): 293–298.
    Margarit E, Bach V, Gomez D et al. (2005) Mutation analysis of Wilson disease in the Spanish population – identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clinical Genetics 68(1): 61–68.
    Materia S, Cater MA, Klomp LW, Mercer JF and LaFontaine S (2012) Clusterin and COMMD1 independently regulate degradation of the mammalian copper ATPases ATP7A and ATP7B. Journal of Biological Chemistry 287(4): 2485–2499.
    Merle U, Weiss KH, Eisenbach C et al. (2010) Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterology 10: 8.
    Miyajima H (2003) Aceruloplasminemia, an iron metabolic disorder. Neuropathology 23(4): 345–350.
    Narindrasorasak S, Kulkarni P, Deschamps P, She YM and Sarkar B (2007) Characterization and copper binding properties of human COMMD1 (MURR1). Biochemistry 46(11): 3116–3128.
    Narindrasorasak S, Zhang X-F, Roberts EA and Sarkar B (2004) Comparative analysis of metal binding characteristics of copper chaperone proteins, Atx1 and Atox1. Bioinorganic Chemistry Applications 2: 105–123.
    Nicastro E, Loudianos G, Zancan L et al. (2009) Genotype-phenotype correlation in Italian children with Wilson's disease. Journal of Hepatology 50(3): 555–561.
    Okada T, Shiono Y, Kaneko Y et al. (2010) High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson's disease. Scandinavian Journal of Gastroenterology 45(10): 1232–1237.
    Panagiotakaki E, Tzetis M, Manolaki N et al. (2004) Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). American Journal of Medical Genetics A 131A(2): 168–173.
    Petrukhin K, Fischer SG, Pirastu M et al. (1993) Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nature Genetics 5(4): 338–343.
    Ramakrishna B, Date A, Kirubakaran C and Raghupathy P (1995) Atypical copper cirrhosis in Indian children. Annals of Tropical Paediatrics 15(3): 237–242.
    Ridge PG, Zhang Y and Gladyshev VN (2008) Comparative genomic analyses of copper transporters and cuproproteomes reveal evolutionary dynamics of copper utilization and its link to oxygen. PLoS One 3(1): e1378.
    Roberts EA (2012) Using metalloproteomics to investigate the cellular physiology of copper in hepatocytes. Metallomics 4(7): 633.
    Roberts EA, Lau CH, da Silveira TR and Yang S (2007) Developmental expression of Commd1 in the liver of the Jackson toxic milk mouse. Biochemistry and Biophysics Research Communications 363(4): 921–925.
    Roberts EA, Robinson BH and Yang S (2008) Mitochondrial structure and function in the untreated Jackson toxic milk (tx-j) mouse, a model for Wilson disease. Molecular Genetics and Metabolism 93(1): 54–65.
    Roberts EA and Sarkar B (2008) Liver as a key organ in the supply, storage, and excretion of copper. American Journal of Clinical Nutrition 88: 851S.
    Rodriguez-Granillo A, Crespo A and Wittung-Stafshede P (2010) Interdomain interactions modulate collective dynamics of the metal-binding domains in the Wilson disease protein. Journal of Physical Chemistry B 114(5): 1836–1848.
    Safaei R, Adams PL, Maktabi MH, Mathews RA and Howell SB (2012) The CXXC motifs in the metal binding domains are required for ATP7B to mediate resistance to cisplatin. Journal of Inorganic Biochemistry 110: 8–17.
    Santhosh S, Shaji RV, Eapen CE et al. (2006) ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson's disease patients. Indian Journal of Gastroenterology 25(6): 277–282.
    Schiefermeier M, Kollegger H, Madl C et al. (2000) The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson's disease. Brain 123(Pt 3): 585–590.
    Schushan M, Bhattacharjee A, Ben-Tal N and Lutsenko S (2012) A structural model of the copper ATPase ATP7B to facilitate analysis of Wilson disease-causing mutations and studies of the transport mechanism. Metallomics 4(7): 669–678.
    Senzolo M, Loreno M, Fagiuoli S et al. (2007) Different neurological outcome of liver transplantation for Wilson's disease in two homozygotic twins. Clinical Neurology and Neurosurgery 109(1): 71–75.
    Seth R, Yang S, Choi S, Sabean M and Roberts EA (2004) In vitro assessment of copper-induced toxicity in the human hepatoma line, Hep G2. Toxicology in Vitro 18(4): 501–509.
    Shah AB, Chernov I, Zhang HT et al. (1997) Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype–phenotype correlation, and functional analyses. American Journal of Human Genetics 61(2): 317–328.
    She YM, Narindrasorasak S, Yang S et al. (2003) Identification of metal-binding proteins in human hepatoma lines by immobilized metal affinity chromatography and mass spectrometry. Molecular and Cellular Proteomics 2(12): 1306–1318.
    Singleton C and Le Brun NE (2007) Atx1-like chaperones and their cognate P-type ATPases: copper-binding and transfer. Biometals 20(3-4): 275–289.
    Slovis TL, Dubois RS, Rodgerson DO and Silverman A (1971) The varied manifestations of Wilson's disease. The Journal of Pediatrics 78(4): 578–584.
    Smith SD, She YM, Roberts EA and Sarkar B (2004) Using immobilized metal affinity chromatography, two-dimensional electrophoresis and mass spectrometry to identify hepatocellular proteins with copper-binding ability. Journal of Proteome Research 3(4): 834–840.
    Squitti R and Polimanti R (2012) Copper hypothesis in the missing hereditability of sporadic Alzheimer's disease: ATP7B gene as potential harbor of rare variants. Journal of Alzheimer's Disease 29(3): 493–501.
    Stapelbroek JM, Bollen CW, van Amstel JK et al. (2004) The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis. Journal of Hepatology 41(5): 758–763.
    Takeshita Y, Shimizu N, Yamaguchi Y et al. (2002) Two families with Wilson disease in which siblings showed different phenotypes. Journal of Human Genetics 47(10): 543–547.
    Thomas GR, Forbes JR, Roberts EA, Walshe JM and Cox DW (1995) The Wilson disease gene: spectrum of mutations and their consequences. Nature Genetics 9(2): 210–217.
    Walshe JM (1989) Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients. Quarterly Journal of Medicine 70(263): 253–263.
    Wan L, Tsai CH, Hsu CM et al. (2010) Mutation analysis and characterization of alternative splice variants of the Wilson disease gene ATP7B. Hepatology 52(5): 1662–1670.
    Weiss KH, Runz H, Noe B et al. (2010) Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. Journal of Inherited Metabolic Disease.
    Wilson DC, Phillips MJ, Cox DW and Roberts EA (2000) Severe hepatic Wilson's disease in preschool-aged children. Journal of Pediatrics 137(5): 719–722.
    Wu ZY, Wang N, Lin MT et al. (2001) Mutation analysis and the correlation between genotype and phenotype of Arg778Leu mutation in Chinese patients with Wilson disease. Archives of Neurology 58(6): 971–976.
    Zappu A, Lepori MB, Incollu S et al. (2012) Feasibility of RNA studies on illegitimate transcription for molecular characterization of splicing mutations in the ATP7B gene: a case report. Molecular and Cellular Probes 26(2): 63–65.
 Further Reading
    van den Berghe PV, Stapelbroek JM, Krieger E et al. (2009) Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin. Hepatology 50(6): 1783–1795.
    Bost M, Piguet-Lacroix G, Parant F and Wilson CM (2012) Molecular analysis of Wilson patients: direct sequencing and MLPA analysis in the ATP7B gene and Atox1 and COMMD1 gene analysis. Journal of Trace Elements in Medicine and Biology 26(2–3): 97–101.
    Davies KM, Hare DJ, Cottam V et al. (2013) Localization of copper and copper transporters in the human brain. Metallomics 5(1): 43–51.
    Folhoffer A, Ferenci P, Csak T et al. (2007) Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease. European Journal of Gastroenterology and Hepatology 19(2): 105–111.
    Lepori MB, Zappu A, Incollu S et al. (2012) Mutation analysis of the ATP7B gene in a new group of Wilson's disease patients: contribution to diagnosis. Molecular and Cellular Probes 26(4): 147–150.
    Lutsenko S, Bhattacharjee A and Hubbard AL (2010) Copper handling machinery of the brain. Metallomics 2(9): 596–608.
    Merle U, Schaefer M, Ferenci P and Stremmel W (2007) Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 56(1): 115–120.
    Roberts EA and Schilsky ML (2008) Diagnosis and treatment of Wilson disease: an update. Hepatology 47(6): 2089–2111.
    Wang Y, Hodgkinson V, Zhu S, Weisman GA and Petris MJ et al. (2011) Advances in the understanding of mammalian copper transporters. Advances in Nutrition 2(2): 129–137.

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Neurobiology of Disease | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease
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Article Title: Molecular Genetics of Wilson Disease
 
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Roberts, Eve A(Apr 2013) Molecular Genetics of Wilson Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024373]