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• W2017061268 abstract "See “Diverse functional properties of Wilson disease ATP7B variants,” by Huster D, Kühne A, Bhattacharjee A, et al, on page 947. See “Diverse functional properties of Wilson disease ATP7B variants,” by Huster D, Kühne A, Bhattacharjee A, et al, on page 947. Wilson disease (WD) is an autosomal-recessive disorder of hepatic copper disposition caused by mutations in the gene ATP7B, located on chromosome 13. In the 100 years since the first description of WD, the clinical pleomorphism of this disease continues to perplex us. WD can present as liver disease, movement disorders, psychiatric disease, or recurrent episodes of hemolytic anemia. Clinical liver disease is diverse, ranging from asymptomatic hepatomegaly or elevation of serum aminotransferases to hepatic steatosis to cirrhosis; however, sometimes the liver disease is negligible despite prominent neurological disability.1Ferenci P. Steindl-Munda P. Vogel W. et al.Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease.Clin Gastroenterol Hepatol. 2005; 3: 811-818Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar Then again, patients with chronic liver disease may not have any neurologic symptoms or brain abnormalities on magnetic resonance imaging. Clinically evident liver disease may precede neurologic manifestations by as much as 10 years. WD may present symptomatically at any age. Although most present between ages 5 and 35, approximately 3% of patients present beyond the fourth decade, with either hepatic or neurologic disease.2Ferenci P. Czlonkowska A. Merle U. et al.Late-onset Wilson's disease.Gastroenterology. 2007; 132: 1294-1298Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar The youngest patient reported with cirrhosis due to WD was 3 years old.3Wilson D.C. Phillips M.J. Cox D.W. Roberts E.A. Severe hepatic Wilson's disease in preschool-aged children.J Pediatr. 2000; 137: 719-722Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar The oldest were diagnosed in their 80s.4Ala A. Borjigin J. Rochwarger A. et al.Wilson disease in septuagenarian siblings: Raising the bar for diagnosis.Hepatology. 2005; 41: 668-670Crossref PubMed Scopus (155) Google Scholar, 5Czlonkowska A. Rodo M. Gromadzka G. Late onset Wilson's disease: therapeutic implications.Mov Disord. 2008; 23: 896-898Crossref PubMed Scopus (53) Google Scholar In the century since Wilson's definitive report, our understanding of WD has progressed dramatically, probably far beyond what Wilson himself might have envisioned. Identification of ATP7B, which is the only gene mutated in all patients with WD studied so far, has permitted structural and cellular studies of the action of its gene product, the Wilson ATPase. This protein has a membrane-spanning region, an ATP-binding region toward the carboxy terminal, and an amino tail comprised of 6 copper-binding units. The Wilson ATPase has at least 2 functions within hepatocytes: it plays an important role in the incorporation of copper into nascent ceruloplasmin and it participates in biliary excretion of excess copper. The observed intracellular relocation of the Wilson ATPase from the trans-Golgi network to the pericanalicular region, depending on ambient intracellular copper concentration, implies that the Wilson ATPase also serves as a sensing and monitoring device for available copper concentration within hepatocytes (Figure 1). Given a prevailing mindset that genetic diseases mandate genetic diagnosis and, ideally, gene therapy as treatment, the expectation of a genetic explanation for clinical diversity in disease presentation and severity seemed obvious. In general, the search for correlations between genotype and phenotype in WD has proved unrewarding. Families have been reported where siblings have divergent clinical WD despite genetic and environmental equivalence.6Takeshita Y. Shimizu N. Yamaguchi Y. et al.Two families with Wilson disease in which siblings showed different phenotypes.J Hum Genet. 2002; 47: 543-547Crossref PubMed Scopus (36) Google Scholar, 7Kegley K.M. Sellers M.A. Ferber M.J. et al.Fulminant Wilson's disease requiring liver transplantation in one monozygotic twin despite identical genetic mutation.Am J Transplant. 2010; 10: 1325-1329Crossref PubMed Scopus (50) Google Scholar Nevertheless, there is some evidence of genotype–phenotype correlation; unfortunately, it is not as fine-grained as initially envisioned. ATP7B mutations which result in absent or nonfunctional Wilson ATPase are associated with severe disease, usually hepatic, and often presenting early in life.8Thomas G.R. Forbes J.R. Roberts E.A. et al.The Wilson disease gene: spectrum of mutations and their consequences.Nat Genet. 1995; 9: 210-217Crossref PubMed Scopus (485) Google Scholar An example of this genotype–phenotype correlation is found with the Atp7b-knockout mouse, which has early and severe liver disease,9Huster D. Finegold M.J. Morgan C.T. et al.Consequences of copper accumulation in the livers of the ATP7B-/- (Wilson disease gene) knockout mice.Am J Pathol. 2006; 168: 423-434Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar especially striking when compared with the tx-j mouse, a spontaneous mouse model for WD with a point mutation, G712D, affecting the second transmembrane region.10Roberts 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: 54-65Crossref PubMed Scopus (70) Google Scholar Available data in affected humans suggest that mutations, which severely interfere with production of the Wilson ATPase, result in early severe liver disease. In the 3-year-old with cirrhosis, her splice mutation near the sixth copper-binding unit was predicted to eliminate Wilson ATPase production completely.3Wilson D.C. Phillips M.J. Cox D.W. Roberts E.A. Severe hepatic Wilson's disease in preschool-aged children.J Pediatr. 2000; 137: 719-722Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar Truncating mutations are associated with lack of holoceruloplasmin production and early onset of clinical disease11Merle U. Weiss K.H. Eisenbach C. et al.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 Gastroenterol. 2010; 10: 8Crossref PubMed Scopus (67) Google Scholar or with Wilsonian acute liver failure.12Okada T. Shiono Y. Kaneko Y. et al.High prevalence of fulminant hepatic failure among patients with mutant alleles for truncation of ATP7B in Wilson's disease.Scand J Gastroenterol. 2010; 45: 1232-1237Crossref PubMed Scopus (31) Google Scholar The usual explanation for the lack of genotype–phenotype correlation in WD is that there are >500 known mutations, and the vast majority of patients with WD are compound heterozygotes. Because most mutations are rare, few data on phenotypes of homozygotes have been reported. Out of the 1235 of mostly Caucasian patients from Central and Eastern Europe in the ongoing study on phenotype–genotype correlations at the Medical University of Vienna, Austria, fewer than one third are homozygotes (Table 1). Only the number of H1069Q homozygotes (accounting for 25% of WD patients) is reasonably large, whereas even the second most common mutation was detected in <1% of the patients. H1069Q homozygotes presented more frequently at an older age with neurologic symptoms.13Stapelbroek J.M. Bollen C.W. van Amstel J.K. et al.The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis.J Hepatol. 2004; 41: 758-763Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Beyond that, no further genotype–phenotype correlations were found.Table 1Summary of Findings in Homozygotic WD Patients in the Vienna Database (427 With Available Data out of 1235 Total)Mutation (Exon)NumberaNumber refers to all cases (symptomatic index casesb + asymptomatic siblings). (% of total)Numberb as index case (% of total)Number with hepatic presentation (% index)Number detected as asymptomatic siblingsH1069Q/H1069Q (14)309 (25.1)262 (24.6)125 (47.7)47R969Q/R969Q (13)11 (0.9)10 (0.9)10 (100)1G710S/G710S (8)10 (0.8)8 (0.7)3 (37.5)23402delC/3402delC (15)7621R778G/R778G (8)6412K844K-fs/K844K-fs (10)6412Other86 (7.0)71 (6.6)48 (67.6)15Other homozygotes: exon 4, n = 3; 5, n = 8; 6, n = 2; 8, n = 17; 9, n = 1; 10, n = 6; 11, n = 2; 12, n = 3; 13, n = 12; 14, n = 6; 15, n = 2; 16, n = 1; 17, n = 6; 18, n = 5; 19, n = 3; and 20, n = 9.a Number refers to all cases (symptomatic index casesb + asymptomatic siblings). Open table in a new tab Other homozygotes: exon 4, n = 3; 5, n = 8; 6, n = 2; 8, n = 17; 9, n = 1; 10, n = 6; 11, n = 2; 12, n = 3; 13, n = 12; 14, n = 6; 15, n = 2; 16, n = 1; 17, n = 6; 18, n = 5; 19, n = 3; and 20, n = 9. Because epigenetic and other genetic factors probably play a role, another strategy for a genetic explanation of clinical diversity is to identify “modifying genes”—genes that exert either an amplifying or ameliorating effect on the mutated gene of interest. Thus far, few gene modifiers of ATP7B have been found. Candidates include apolipoprotein E,14Schiefermeier M. Kollegger H. Madl C. et al.The impact of apolipoprotein E genotypes on age at onset of symptoms and phenotypic expression in Wilson's disease.Brain. 2000; 123: 585-590Crossref PubMed Scopus (122) Google Scholar the human prion gene,15Merle U. Stremmel W. Gessner R. Influence of homozygosity for methionine at codon 129 of the human prion gene on the onset of neurological and hepatic symptoms in Wilson disease.Arch Neurol. 2006; 63: 982-985Crossref PubMed Scopus (36) Google Scholar and 5,10-methylenetetrahydrofolate reductase (MTHFR).16Gromadzka G. Rudnicka M. Chabik G. et al.Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease.J Hepatol. 2011; 55: 913-919Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar The data were obtained in small cohorts; some findings were not reproduced by others. The overall contribution of such genetic factors to the disease heterogeneity seems minimal but remains to be fully investigated. Female gender may account for some aspects of the clinical severity of WD. Females are more likely to develop the acute liver failure presentation and may develop liver disease earlier.17Ferenci P. Merle U. Czlonkowska A. et al.Impact of gender on the clinical presentation of Wilson disease.J Hepatol. 2010; 52: S31-S32Abstract Full Text PDF Google Scholar Within some circles, there has been movement away from putting the main, if not exclusive, focus on genes.18Keller E.F. The mirage of a space between nature and nurture. Duke University Press, Durham, NC2010Crossref Google Scholar The notion that a gene mutation generates a defective gene product which then results in a disease state can be simplistic. Part of the impetus for taking the spotlight off genes is that in fact it has become progressively difficult to define exactly what a gene is. The gene may be more than simply the identified DNA structural coding region and its contiguous upstream regulating region. Moreover, genes have to be expressed to make their key contribution, and that expression takes place in cells/tissues and results ultimately in the formation of proteins. In turn, numerous proteins and other cellular components can modulate how DNA operates. For WD, this broader conceptual framework would involve more detailed functional studies of the Wilson ATPase itself. Accordingly, in this issue of Gastroenterology, Huster et al19Huster D. Kühne A. Bhattacharjee A. Diverse functional properties of Wilson disease ATP7B variants.Gastroenterology. 2012; 142: 947-956Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar have investigated the functional properties of 28 mutations of ATP7B. Gene products were expressed using the baculovirus expression system in Sf9 insect cells; both the phosphorylating and transporting functions of the Wilson ATPase were quantified. What they found was marked variability between mutant Wilson ATPases in terms of protein stability, cellular localization, catalytic, and transport capability. In some cases, as with the A874V mutation, the functional outcome differed from what was expected from the predicted protein structure. They also described what might be called the “shifting phenotype” phenomenon: increasing cellular concentration of copper facilitated exit of the G875R mutant from the endoplasmic reticulum and its appropriate targeting to the trans-Golgi network and thus enhanced function. Seeking direct correlation between changes in genotype and changes in phenotype makes the assumption that phenotypic changes occur exclusively because of changes in genotype. A “shifting phenotype” shows that this assumption is faulty. A potential drawback with this experimental design is that the Sf9 cell is sufficiently different from mammalian cells that the results may not be extrapolated to humans. Clearly, this objection is the flip side to what is attractive about the experimental system: the Wilson ATPase is isolated as a functioning protein. The yeast complementation system, which has been highly informative, is also somewhat vulnerable to similar criticism.20Forbes J.R. Cox D.W. Functional characterization of missense mutations in ATP7B: Wilson disease mutation or normal variant?.Am J Hum Genet. 1998; 63: 1663-1674Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 21Hsi G. Cullen L.M. Glerum D.M. et al.Functional assessment of the carboxy-terminus of the Wilson disease copper-transporting ATPase, ATP7B.Genomics. 2004; 83: 473-481Crossref PubMed Scopus (19) Google Scholar For assessment of one aspect of ATPase function in patients with WD, a functional test is available, although now rarely utilized. Measuring ceruloplasmin activity as a ferroxidase reflects the competence of the liver to produce enzymatically active, copper-bearing holo-ceruloplasmin. The diagnostic sensitivity of ceruloplasmin measured by the oxidase assay has recently been reiterated.22Merle U. Eisenbach C. Weiss K.H. et al.Serum ceruloplasmin oxidase activity is a sensitive and highly specific diagnostic marker for Wilson's disease.J Hepatol. 2009; 51: 925-930Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Comparison of the studies presented here in Sf9 cells with enzymatic holoceruloplasmin activities in patients might be of great interest. These studies point to an important problem in WD, namely, how to define phenotype. Genetic association studies require phenotype to be defined as accurately as possible. In many cases, it is not difficult to identify WD in patients with classic neurologic or hepatic findings. Unfortunately, in approximately half of all patients the typical signs of WD may be absent.23Steindl P. Ferenci P. Dienes H.P. et al.Wilson's disease in patients presenting with liver disease: a diagnostic challenge.Gastroenterology. 1997; 113: 212-218Abstract Full Text PDF PubMed Scopus (317) Google Scholar In patients presenting with neurologic symptoms, exclusion of longstanding asymptomatic liver disease requires a detailed evaluation, including a liver biopsy. Asymptomatic siblings or patients with incidentally detected liver disease may never manifest neurologic disease, which would have developed if they had been diagnosed at a later time. For example, an 18-year-old asymptomatic woman with the accidental finding of a Kayser–Fleischer ring received no treatment and developed neurologic symptoms 27 years later.2Ferenci P. Czlonkowska A. Merle U. et al.Late-onset Wilson's disease.Gastroenterology. 2007; 132: 1294-1298Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar Delay in diagnosing WD in patients with neuropsychiatric presentations is frequent, sometimes on the order of a decade.24Merle U. Schaefer M. Ferenci P. et al.Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study.Gut. 2007; 56: 115-120Crossref PubMed Scopus (420) Google Scholar Age of symptom onset is a poor tool to study phenotype, at least in adult WD patients, although it may be highly informative in young children. Likewise, defining phenotype at the cellular level is not entirely obvious. Identifying lack of expressed gene product is rather easy. Assessing the degree of protein misfolding is a structural phenotypic feature potentially of therapeutic interest. Classifying the functional phenotype is less straightforward. The observations in Sf9 cells suggest that the functional phenotype could be characterized in terms of phosphorylating capacity or copper transport. Other Wilson ATPase functions of interest might include movement from the trans-Golgi network to the pericanalicular zone, or binding to the copper chaperone ATOX1, or interaction with other cellular proteins of the Wilson ATPase interactome. In summary, these cell physiology studies redirect the focus from what specific mutations in the ATP7B gene might portend to how the gene product actually functions in a defined cellular milieu. Although disease-causing mutations lead to accumulation of copper in hepatocytes, they do not have an exclusive explanatory role for all the features of WD. Phenotype has to be characterized as a complex function at the cellular level. For understanding the clinical physiology of WD, we require (a) dynamic assay(s) of hepatocellular copper handling to determine the pathophysiology of ATP7B mutations more precisely. We also need fine-tuned phenotypic classification of WD. This should encourage worldwide cooperation to define phenotypes and identify factors associated with the spectrum of clinical presentations in WD. Diverse Functional Properties of Wilson Disease ATP7B VariantsGastroenterologyVol. 142Issue 4PreviewWilson disease is a severe disorder of copper metabolism caused by mutations in ATP7B, which encodes a copper-transporting adenosine triphosphatase. The disease presents with a variable phenotype that complicates the diagnostic process and treatment. Little is known about the mechanisms that contribute to the different phenotypes of the disease. Full-Text PDF" @default.
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• W2017061268 title "Defining Wilson Disease Phenotypes: From the Patient to the Bench and Back Again" @default.
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