Journal of Hepatology
Volume 34, Issue 1 , Pages 165-171, January 2001

The Wilson's disease gene and phenotypic diversity

  • Stephen M Riordan

      Affiliations

    • Institute of Hepatology, University College London and University College London Hospitals, 69–75 Chenies Mews, London WC1E 6HX, UK
    • Department of Gastroenterology, The Prince of Wales Hospital, Sydney, Australia
    • ,
  • Roger Williams

      Affiliations

    • Institute of Hepatology, University College London and University College London Hospitals, 69–75 Chenies Mews, London WC1E 6HX, UK
    • Corresponding Author InformationCorresponding author. Tel.:+44-0207-380-0401; fax: +44-0207-380-0405

Article Outline

 

Copper is an essential component of many enzymes, including superoxide dismutase, lysyl oxidase, dopa-b-hydroxylase, tyrosinase and cytochrome c oxidase, and is required for such diverse processes as oxidative metabolism, neurotransmitter synthesis, free radical detoxification, iron uptake and maturation of connective tissue [1], [2], [3]. However, this metal is only required in trace amounts and is toxic in larger quantities. Harmful effects of excessive tissue copper include the generation of free radicals with resultant depletion of cellular stores of glutathione and oxidation of lipid, enzymes and cytoskeletal proteins [4]. CD95-mediated cellular apoptosis has also been reported [5]. Since dietary copper intake generally exceeds requirements, an effective means of copper clearance is required. This is achieved via the hepatobiliary route in humans [6]. In Wilson's disease, biliary excretion of copper along with its incorporation into ceruloplasmin are impaired, leading to excessive copper accumulation in hepatocytes and elsewhere. This autosomal recessive disorder is one of the rarest inborn errors of metabolism, with a worldwide frequency of between 1 in 30 000 and 1 in 100 000 live births [6], [7]. Since the gene for Wilson's disease, termed ATP7B, was first reported in 1993 [8], [9], [10], at least 200 different disease-specific mutations have been described, including single base insertions and deletions, frame-shifts and missense, non-sense and splice site mutations [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Recent studies have shown that the most common mutation, His1069Gln, is present in over 70% of Polish and 60% of Austrian patients with Wilson's disease [21], [22] and accounts for between 10 and 40% of all mutations identified in patients of other European and North American origin [12], [13], [14], [16], [18], [23], [24]. The His1069Gln mutation and four others together account for 74% of Wilson's disease chromosomes in patients of Greek descent [19]. In contrast, the His1069Gln mutation has been documented only rarely, if at all, in patients from India [25], Asia [12] and Sardinia [16], [17]. A single mutation consisting of a 15 nucleotide deletion in the 5′UTR of the Wilson's disease gene accounts for over 60% of Wilson's disease chromosomes in Sardinians, with an additional four mutations found on a further 25% [16], [17]. However, over half of all known mutations occur only rarely in any given population [9], [12], [13], [14], [15], [16], [18], [19]. Most patients are compound heterozygotes, possessing alleles with two different mutations [12], [13], [14], [15], [16], [18], [26]. Recent investigations pertaining to the Wilson's disease gene and its protein product have led to both a substantial increase in knowledge of mechanisms underlying disease pathogenesis and improved accuracy in diagnosis. Whether there exist relationships between specific mutational defects and divergence in phenotypic expression accounting for the protean clinical manifestations of this disorder is the main question addressed in this review.

The approximately 7.5 kilobase Wilson's disease gene transcript encodes a 1465 amino acid protein of the P-type adenosine triphosphatase family which contains six copper-binding regions, an adenosine triphosphate (ATP) domain, a transmembrane cation channel, a phosphorylation region and a transduction domain responsible for the conversion of energy of ATP hydrolysis to cation transport [4], [8], [9], [10], [11], [27]. Copper binding occurs via cysteine residues [28], [29] and may be co-operative, based on competitive zinc binding experiments [29]. The copper-binding domains of the ATP7B protein remove copper from cytosolic ligands and transport it within hepatocytes prior to its subsequent excretion [30]. These domains may also function as copper sensors [29], [31], [32]. In the hepatoblastoma-derived HepG2 cell line, the ATP7B protein is synthesised as a single 165 kDa protein localised to the trans-Golgi apparatus [33], [34]. Cellular exposure to high copper levels has been shown to result in reversible intra-cellular trafficking of the ATP7B protein from this site to a post-Golgi vesicular compartment in close proximity to the biliary canalicular plasma membrane [32], [33], [35]. This copper-induced shift in location may reflect a change in physiological function of the ATP7B protein, namely from the translocation of copper to the Golgi apparatus for incorporation into apoceruloplasmin to form ceruloplasmin under steady-state conditions to the transportation of copper to secretory vesicles for its eventual excretion into biliary canaliculi in the setting of copper excess [11], [27], [29]. A role for the ATP7B protein in copper transport is supported by evidence that its expression in Menkes patient fibroblast cell lines reduces copper accumulation in these cells [36], [37].

Recent data suggest that those copper-binding motifs closest to the transmembrane channel of the ATP7B protein are directly involved in copper transport, by transferring copper to residues within the channel for subsequent translocation across the membrane. Other N-terminal motifs likely induce redistribution of the ATP7B protein within the cell in response to cytosolic copper concentrations [27]. A 140 kDa ATP7B product, likely formed after proteolytic cleavage of the full length ATP7B protein, has recently been found in mitochondria, suggesting a possible role for this protein in cellular energy production [38]. Further characterisation of processes responsible for docking and trafficking of the ATP7B protein, along with the final steps of copper excretion via biliary canaliculi, will be important for full understanding of not only the precise role of dysfunctional ATP7B in the pathogenesis of Wilson's disease but also mechanisms of copper homeostasis in general.

The ATP7B protein, as well as in hepatocytes, is expressed in a wide variety of tissues including kidney, placenta, brain, heart, lung, muscle and pancreas [4], [8], [10], [35], [39], [40]. In an animal model of Wilson's disease, both messenger RNA for ATP7B and the ATP7B protein have recently been localised to neuronal cells of the hippocampus, olfactory bulbs, cerebellum, cerebral cortex and brainstem nuclei. High levels of copper were also found at these sites, compatible with the notion that dysfunctional ATP7B protein at a local level is intimately related to copper accumulation and the development of the cerebral manifestations of Wilson's disease [41]. Nonetheless, reports of reversal of neuropsychiatric abnormalities in Wilson's disease patients following liver transplantation indicate that the primary genetic defect leading to copper accumulation resides in the liver [42], [43], with successful liver replacement presumably facilitating the mobilisation of copper from extrahepatic sites. Instances of resolution of Kayser–Fleischer rings in this setting [42] support this thesis. Recurrence of copper-associated liver damage in a transplanted liver has not been reported. Of course, liver transplantation does not eliminate the possibility of transmission of the Wilson's disease gene to offspring. Although the defect leading to the accumulation of copper is present at birth, symptoms of any sort uncommonly develop before the age of 5 years.

Clinical manifestations of Wilson's disease are extraordinarily diverse, with wide variation in hepatic abnormalities and an inconsistent relationship between severity of liver disease and the classical neurological disturbances. The original view of Kinnear Wilson that all patients have an underlying cirrhosis which is of importance in relation to the development of neurological damage [44] is not true, although over 80% of presentations within the first decade of life, and 40–70% of presentations overall, are related to liver involvement [4], [45], [46], [47], [48]. Histological abnormalities are non-diagnostic, mimicking a broad range of other acute and chronic hepatic disorders. These include an acute self-limiting hepatitis, chronic active hepatitis and cirrhosis. In the earliest stages of hepatocellular injury, ultrastructural abnormalities involving the endoplasmic reticulum, mitochondria, peroxisomes and nuclei, along with diminished mitochondrial enzyme activities leading to lipid peroxidation and triglyceride accumulation within hepatocytes, have been identified [49]. The rate of progression from fatty infiltration to cirrhosis is variable, with no relation between age and likelihood of cirrhosis [50]. Wilson's disease may also present as fulminant hepatic failure, especially in females [42], [51], [52], [53]. Such patients have underlying but previously asymptomatic chronic liver disease, although not always as advanced as cirrhosis. With the exception of previously treated patients who become non-compliant with chelation therapy, fulminant hepatic failure in Wilson's disease occurs suddenly and without a recognisable precipitating factor, although the female predominance suggests that hormonal factors may in some way be involved. The presence of splenomegaly and Coombes-negative haemolysis, the latter due to release of large quantities of copper from necrotic hepatocytes, is of most clinical value in differentiating fulminant hepatic failure due to Wilson's disease from that due to other aetiologies. Its recognition is important in view of the uniformly poor prognosis unless liver transplantation is performed as a matter of urgency.

It is uncommon for neurological involvement to become manifest before puberty [54]. Approximately 75% of patients presenting after the age of 20 years have developed neuropsychiatric complications [45], [46], [47]. Overall, in the order of 25% of patients manifest both hepatic and neuropsychiatric involvement at the time of initial evaluation [4]. Four main neurological syndromes have been described, including parkinsonian, pseudosclerotic, dystonic and choreic [54]. The earliest symptoms of neurological Wilson's disease include difficulty in speaking, drooling and clumsiness of the hands, often associated with a change in personality. Almost never does the disease present with abnormalities of gait as a first symptom. Nonetheless, neuropsychiatric abnormalities due to deposition of copper in the central nervous system must be distinguished from those of chronic hepatic encephalopathy, especially in patients with advanced hepatic involvement and/or portosystemic shunting [55], [56]. It is currently unknown whether the sensitivity of basal ganglia to copper toxicity in Wilson's disease is in some way exacerbated by the additional propensity for manganese deposition at these sites in chronic hepatic encephalopathy [57], [58]. Presentation with primarily renal, skeletal, cardiac, ophthalmologic, endocrinologic or dermatologic symptoms is uncommon, although such involvement often becomes evident as the disease progresses [4]. Conversely, more aggressive screening of especially younger family members of affected patients has led to an increasing number of patients being diagnosed while at an asymptomatic stage.

Presentation can occasionally be delayed to as late as the sixth decade [50], [59], [60], [61], [62], [63], [64]. Hepatic abnormalities, although not necessarily established cirrhosis, are generally clinically apparent and, interestingly, not all such patients have associated neurological symptoms or signs, suggesting a more slowly progressive form of disease than generally appreciated. Indeed, some patients in this age range have even been identified at an asymptomatic stage, after the diagnosis of Wilson's disease had been made in a younger family member. Conversely, presentation with acute liver failure with fatal outcome has been reported in a patient as old as 58 years. The lack of documented instances of hepatocellular carcinoma (HCC) in patients presenting at later age is also of interest. It is generally considered that the incidence of HCC in patients with Wilson's disease is not higher than that in the general population, unlike with all other aetiologies of cirrhosis. However, studies in the Long-Evans-Cinnamon rat, an animal model of human Wilson's disease [65], indicate that long-term, elevated hepatic copper levels do lead to HCC in aged animals [66]. Both the initiating hepatocellular injury and the late occurrence of neoplastic transformation in the animal model are prevented by treatment with penicillamine [67] and it has been proposed that the rarity of complicating HCC in Wilson's disease is a reflection of this protective effect of early chelation therapy [26]. However, this complication was rare even in the pre-penicillamine era. The fact that HCC has not been apparent in untreated patients as old as 58 years, even in the setting of established cirrhosis, further suggests that it is not the early institution of chelation treatment alone which protects patients with Wilson's disease from this complication.

Assessment of whether diversity of phenotypic expression in Wilson's disease is related to allelic heterogeneity is hampered by the large number of mutations of the ATP7B gene so far detected. Nonetheless, it has been supposed that specific mutations may affect individual processes of copper sensing, copper-mediated trafficking and copper transport and that such variability may contribute to the diverse clinical manifestations of Wilson's disease [35], analogous to the situation with different cystic fibrosis transmembrane conductance regulator mutations in patients with cystic fibrosis [68]. Bearn [69] and Cox et al. [70] in 1960 and 1972, respectively, had reported phenotypic variability among some ethnic groups, which was considered likely on the basis of genetic heterogeneity. More recently, an analysis of 15 symptomatic patients from European, British, Middle Eastern and Asian families found to be homozygous for particular mutations has suggested that at least part of the wide phenotypic variation observed in Wilson's disease may be explained on a genetic basis. In particular, the average age of onset of symptoms was found to be 7.2 years, and as early as 3 years, in patients homozygous for mutations predicted to destroy the function of the gene (insertion, deletion, non-sense or frame-shift), while that in patients with less severe abnormalities, such as the most commonly encountered His1069Gln mutation, was approximately 10 years later [12]. Similarly, Shah et al. [13] found in North American patients an average age of onset of 20 years in homozygotes for the His1069Gln mutation compared with 15 years in compound heterozygotes, in keeping with trends reported by Maier-Dobersberger et al. [21] (24 years vs. 17 years) and Czlonkowska et al. [22] (31 years versus 23 years) in Austrian and Polish patients, respectively. All four His1069Gln homozygotes in the Northern European series of Waldenstrom et al. [24] were aged over 20 years at the time of diagnosis.

No definite association between genotype and mode of presentation or subsequent clinical course has been established. Most Dutch homozygotes for the His1069Gln mutation in one series presented with neuropsychiatric symptoms [15], while neurological presentations were significantly more common than hepatic in His1069Gln homozygotes compared to either compound heterozygotes or His1069Gln-negative patients in a predominantly Austrian series representing 90% of all known Wilson's disease families in that country [71]. A trend between homozygosity for the His1069Gln mutation and neurological presentation has also been reported in a Polish study [22]. Nonetheless, these findings have not been borne out by experience with other European and North American counterparts, in whom hepatic and neuropsychephiatric presentations have been similarly represented [12], [13], [24]. An association between the Asn1270Ser mutation and a fulminant presentation has been described in Costa Rican patients, although any causal association between this genotype and fulminant liver failure remains unclear as the single non-Costa Rican patient with this mutation did not present in this way [13]. The large number of mutations and high prevalence of compound heterozyotes reported to date among various Mediterranean populations [14], [15], [16], [18] render genotype-phenotype correlation analysis difficult. Single Turkish patients homozygous for Gln110ter and Ser1363Phe mutations presented with neurological symptoms at age 10 years and 12 years, respectively, while one Turkish and one Italian patient homozygous for Cys1104Phe and Val1262Phe, respectively, presented with hepatic abnormalities at age 9–10 years [14]. Further genotype-phenotype correlation analyses are currently underway in Sardinian patients following the recent determination of the common deletional mutation in the 5′UTR of the Wislon's disease gene. Preliminary data indicate that both neurological and hepatic presentations occur [17]. Importantly, patients in whom the relationship between genotype and phenotype has been reported so far have been children, adolescents or young adults. Genetic analysis of patients presenting at later age will be particularly important to further define the possible influence of ATP7B genotype on phenotypic diversity in this disorder.

At least some phenotypic variability in Wilson's disease is likely due to additional factors, as demonstrated by differences in mode of presentation, hepatic copper content, ceruloplasmin levels and disease course in patients with the same ATP7B mutations, even within the same family and in identical twins [12], [13], [72], [73]. Dietary copper intake, intestinal metallothionein inducibility and capacity for countering copper stress at the cellular level via glutathione and heat shock protein pathways [12], [74] may all be important factors modulating the phenotypic response. Consideration of these variables in a range of Wilson's disease patients encompassing the full spectrum of clinical manifestations and of known ATP7B genotype will, in particular, be critical to determining interactions between ATP7B mutations and environmental and other factors which possibly influence phenotype. Recent data suggest that apolipoprotein E (ApoE) genotype may influence disease expression. In particular, Wilson's disease patients homozygous for the His1069Gln mutation who were also homozygous for the ApoE genotype ε3/3 were found to develop symptoms between 5 and 11 years later than those with genotypes other than ApoE ε3/3. Conversely, no association between ApoE genotype and phenotypic expression at presentation was apparent [71]. Copper-binding, antioxidant and membrane-stabilising properties of the ApoE 3 protein [75], [76] have been proposed as possible mechanisms by which the ApoE ε3/3 genotype may confer advantage by delaying clinical manifestations of Wilson's disease [71]. Genetic variations in expression of factors necessary for the intracellular sensing and trafficking functions of the ATP7B protein, including the recently identified HAH1 chaperone protein essential for delivery of cytosolic copper to the ATP7B protein [77], [78], should also be examined in future for any possible contribution to the clinical heterogeneity of Wilson's disease patients. Recent studies performed in Saccharomyces cerevisiae and mammalian cells have suggested that the direct, copper-dependent interaction between HAH1 and the ATP7B protein via copper-binding cysteine ligands in the amino terminus of HAH1 is an essential mechanism for copper trafficking to the secretory pathway of all cells. Mutations which occur in the copper-binding domain of the Wilson's disease gene lead to impairment of this interaction and disruption of cellular copper homeostasis [79], [80].

Standard biochemical and ophthalmological screening in patients with otherwise unexplained liver disease or in the context of a known family history of Wilson's disease may yield a diagnostic pattern of abnormality, although interpretation is often problematic owing to the potential for both false-negative and false-positive results. While a serum ceruloplasmin level less than 20 mg/dl in association with either Kayser–Fleischer rings or an hepatic copper content in excess of 250 mg/g dry weight is sufficient to make a diagnosis of Wilson's disease, no single abnormality in isolation is diagnostic. Kayser–Fleischer rings are absent at the time of presentation in 27–73% of patients with isolated hepatic disease [50], [81], [82], while corneal copper deposits may also be found with cholestatic disorders unrelated to Wilson's disease. Hepatic copper concentrations in the Wilson's disease range may also occur in this circumstance. Conversely, hepatic copper content may occasionally be below the diagnostic level in Wilson's disease patients, especially in pre-symptomatic individuals and in the fulminant setting [77], [81], [83]. Ceruloplasmin levels fall within the reference range in up to 15% of Wilson's disease patients, while low levels are also found in hereditary hypoceruloplasminaemia, severe malnutrition, protein-losing enteropathy, nephrotic syndrome, severe non-Wilsonian liver damage and about 20% of heterozygote carriers [54], [77], [81]. That a low ceruloplasmin level alone is clearly not useful as a screening tool for Wilson's disease in those with liver disease is illustrated by the fact that three times as many heterozygote carriers and over 10 times as many patients with liver damage due to other aetiologies are identified in this way than those with true Wilson's disease [84]. Alternative biochemical tests also have limitations. While incorporation of radiocopper into ceruloplasmin is generally abnormal even in those Wilson's disease patients with normal ceruloplasmin levels, considerable overlap with heterozygote carriers has been reported [85]. The serum copper level is also unreliable, being increased in fulminant presentations, while an increased urinary copper level is not specific for Wilson's disease [4], although measurement of urinary copper excretion has been strongly recommended as a diagnostic test in paediatric practice, especially after penicillamine challenge [86].

Genetic analysis techniques allow discrimination with certainty between the homozygous/compound heterozygous and heterozygous carrier states in those patients with a family history of Wilson's disease in whom doubt otherwise exists, provided that DNA is available from the proband. While the existence of a large number of mutations of the Wilson's disease gene and the common necessity of searching for two different abnormalities currently render genetic diagnosis problematic in patients without an affected family member, accurate molecular diagnosis can readily be achieved in first-degree relatives of a known patient using polymerase chain reaction-based DNA linkage analysis involving highly polymorphic microsatellite markers. A close correlation exists between disease-specific mutations and distinct haplotypes which predict the presence of disease with almost 100% accuracy [9], [87], [88]. Haplotype or direct mutation analysis may be feasible even in the absence of DNA availability from a proband in those populations in which a limited number of mutations are known to account for a large proportion of Wilson's disease cases, such as Sardinian and Greek [16], [17], [19]. Accurate differentiation between homozygotes/compound heterozygotes and heterozygote carriers, especially at an asymptomatic stage, is extremely important, since early institution of life-long chelation therapy which nonetheless may carry potentially serious side-effects is essential in the former group if progressive liver damage and disabling neurological manifestations are to be prevented, while no treatment is necessary for heterozygote carriers, in whom no adverse clinical consequence is recognised.

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PII: S0168-8278(00)00028-3

doi:10.1016/S0168-8278(00)00028-3

Journal of Hepatology
Volume 34, Issue 1 , Pages 165-171, January 2001

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