Molecular Genetics of Wilson Disease

Abstract

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 α1‐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 . © 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 . © 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 based on de Bie et al.. © 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. with additional data as indicated from Wu et al., and Gupta et al.. © Elsevier.

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Further Reading

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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]