The Wilson's disease gene and phenotypic diversity
2001; Elsevier BV; Volume: 34; Issue: 1 Linguagem: Inglês
10.1016/s0168-8278(00)00028-3
ISSN1600-0641
AutoresStephen M. Riordan, Roger Williams,
Tópico(s)Iron Metabolism and Disorders
ResumoCopper 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 [1Bull P.C. Cox D.W. Wilson disease and Menkes disease: new handles on heavy-metal transport.Trends Genet. 1994; 10: 246-252Abstract Full Text PDF PubMed Scopus (273) Google Scholar, 2Agarwal K. Sharma A. Talukdar G. Effects of copper on mammalian cell components.Chem Biol Interact. 1989; 69: 1-16Crossref PubMed Scopus (84) Google Scholar, 3Vulpe C.D. Packman S. Cellular copper transport.Annu Rev Nutr. 1995; 15: 293-322Crossref PubMed Scopus (241) Google Scholar]. 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]Gollan J.L. Gollan T.J. Wilson diesease in 1998: genetic, diagnostic and therapeutic aspects.J Hepatol. 1998; 28: 28-36Abstract Full Text PDF PubMed Google Scholar]. CD95-mediated cellular apoptosis has also been reported [[5]Strand S. Hofmann W.J. Grambihler A. Hug H. Volkmann M. Otto G. et al.Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis.Nat Med. 1998; 4: 588-593Crossref PubMed Scopus (227) Google Scholar]. 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]Sheinberg I.H. Sternlieb I. Wilson disease and idiopathic copper toxicosis.Am J Clin Nutr. 1996; 63: 842S-845SPubMed Google Scholar]. 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 [6Sheinberg I.H. Sternlieb I. Wilson disease and idiopathic copper toxicosis.Am J Clin Nutr. 1996; 63: 842S-845SPubMed Google Scholar, 7Danks D.M. Disorders of copper transport.in: Beaudet A.L. Sly W.S. Valle D. Metabolic basis of inherited disease. McGraw-Hill, New York1989: 1411-1431Google Scholar]. Since the gene for Wilson's disease, termed ATP7B, was first reported in 1993 [8Bull P.C. Thomas G.R. Rommens J.M. Forbes J.R. Cox D.W. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.Nat Genet. 1993; 5: 327-337Crossref PubMed Scopus (1688) Google Scholar, 9Petrukhin K. Fischer S.G. Pirastu M. Tanzi R.E. Chernov I. Devoto M. et al.Mapping, cloning and genetic characterization of the region containing the Wilson disease gene.Nat Genet. 1993; 5: 338-343Crossref PubMed Scopus (468) Google Scholar, 10Tanzi R.E. Petrukhin K. Chernov I. Pellequer J.L. Wasco W. Ross B. et al.The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.Nat Genet. 1993; 5: 344-350Crossref PubMed Scopus (1174) Google Scholar], 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 [11Terada K. Schilsky M.L. Miura N. Sugiyama T. ATP7B (WND) protein.Int J Biochem Cell Biol. 1998; 30: 1063-1067Crossref PubMed Scopus (70) Google Scholar, 12Thomas G.R. Forbes J.R. Roberts E.A. Walshe J.M. Cox D.W. The Wilson disease gene: spectrum of mutations and their consequences.Nat Genet. 1995; 9: 210-217Crossref PubMed Scopus (487) Google Scholar, 13Shah A.B. Chernov I. Zang H.T. Ross B.M. Das K. Lutsenko S. et al.Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation and functional analyses.Am J Hum Gen. 1997; 61: 317-328Abstract Full Text PDF PubMed Scopus (302) Google Scholar, 14Loudianos G. Dessi V. Lovicu M. Angius A. Altuntas B. Giacchino R. et al.Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.J Med Genet. 1999; 36: 833-836PubMed Google Scholar, 15Loudianos G. Dessi V. Angius A. Lovicu M. Loi A. Deiana M. et al.Wilson disease mutations associated with uncommon haplotypes in Mediterranean patients.Hum Genet. 1996; 98: 640-642Crossref PubMed Scopus (40) Google Scholar, 16Figus A. Angius A. Loudianos G. Bertini C. Dessi V. Loi A. et al.Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.Am J Hum Genet. 1995; 57: 1318-1324PubMed Google Scholar, 17Loudianos G. Dessi V. Lovicu M. Angius A. Figus A. Lilliu F. et al.Molecular characterization of Wilson disease in the Sardinian population - evidence of a founder effect.Hum Mutat. 1999; 14: 294-303Crossref PubMed Scopus (129) Google Scholar, 18Loudianos G. Dessi V. Lovicu M. Angius A. Nurchi A. Sturniolo G.C. et al.Further delineation of the molecular pathology of Wilson disease in the Mediterranean population.Hum Mutat. 1998; 12: 89-94Crossref PubMed Scopus (79) Google Scholar, 19Loudianos G. Dessi V. Lovicu M. Angius A. Kanavakis E. Tzetis M. et al.Haplotype and mutation analysis in Greek patients with Wilson disease.Eur J Hum Genet. 1998; 6: 487-491Crossref PubMed Scopus (47) Google Scholar, 20http://www.medgen.med.ualberta.ca/database.htmlGoogle Scholar]. 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 [21Maier-Dobersberger T. Fenenci P. Polli C. Balac P. Dienes H.P. Kaserer K. et al.Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction.Ann Int Med. 1997; 127: 21-26Crossref PubMed Scopus (115) Google Scholar, 22Czlonkowska A. Rodo M. Gajda J. Ploos van Amstel H.K. Juyn J. Houwen R.H. Very high frequency of the His1069Gln mutation in Polish Wilson disease patients.J Neurol. 1997; 244: 591-599Crossref PubMed Scopus (48) Google Scholar] and accounts for between 10 and 40% of all mutations identified in patients of other European and North American origin [12Thomas G.R. Forbes J.R. Roberts E.A. Walshe J.M. Cox D.W. The Wilson disease gene: spectrum of mutations and their consequences.Nat Genet. 1995; 9: 210-217Crossref PubMed Scopus (487) Google Scholar, 13Shah A.B. Chernov I. Zang H.T. Ross B.M. Das K. Lutsenko S. et al.Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation and functional analyses.Am J Hum Gen. 1997; 61: 317-328Abstract Full Text PDF PubMed Scopus (302) Google Scholar, 14Loudianos G. Dessi V. Lovicu M. Angius A. Altuntas B. Giacchino R. et al.Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.J Med Genet. 1999; 36: 833-836PubMed Google Scholar, 16Figus A. Angius A. Loudianos G. Bertini C. Dessi V. Loi A. et al.Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.Am J Hum Genet. 1995; 57: 1318-1324PubMed Google Scholar, 18Loudianos G. Dessi V. Lovicu M. Angius A. Nurchi A. Sturniolo G.C. et al.Further delineation of the molecular pathology of Wilson disease in the Mediterranean population.Hum Mutat. 1998; 12: 89-94Crossref PubMed Scopus (79) Google Scholar, 23Houwen R.H. Juyn J. Hoogenraad T.U. Ploos van Amstel J.K. Berger R. H747Q mutation in Wilson disease is associated with late, neurological presentation.J Med Genet. 1995; 32: 480-482Crossref PubMed Scopus (54) Google Scholar, 24Waldenstrom E. Lagerkvist A. Dahlman T. Westermark K. Landegren U. Efficient detection of mutations in Wilson disease by manifold sequencing.Genomics. 1996; 37: 303-309Crossref PubMed Scopus (96) Google Scholar]. The His1069Gln mutation and four others together account for 74% of Wilson's disease chromosomes in patients of Greek descent [[19]Loudianos G. Dessi V. Lovicu M. Angius A. Kanavakis E. Tzetis M. et al.Haplotype and mutation analysis in Greek patients with Wilson disease.Eur J Hum Genet. 1998; 6: 487-491Crossref PubMed Scopus (47) Google Scholar]. In contrast, the His1069Gln mutation has been documented only rarely, if at all, in patients from India [[25]Morris P.A. Curtis D. Quarrell O.W. Peake I. Goodeve A. Tanner M.S. Screening for the common mutation His1069Gln in the Wilson's disease gene.Ger J Gastroenterol. 1995; 8: 476Google Scholar], Asia [[12]Thomas G.R. Forbes J.R. Roberts E.A. Walshe J.M. Cox D.W. The Wilson disease gene: spectrum of mutations and their consequences.Nat Genet. 1995; 9: 210-217Crossref PubMed Scopus (487) Google Scholar] and Sardinia [16Figus A. Angius A. Loudianos G. Bertini C. Dessi V. Loi A. et al.Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.Am J Hum Genet. 1995; 57: 1318-1324PubMed Google Scholar, 17Loudianos G. Dessi V. Lovicu M. Angius A. Figus A. Lilliu F. et al.Molecular characterization of Wilson disease in the Sardinian population - evidence of a founder effect.Hum Mutat. 1999; 14: 294-303Crossref PubMed Scopus (129) Google Scholar]. 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% [16Figus A. Angius A. Loudianos G. Bertini C. Dessi V. Loi A. et al.Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.Am J Hum Genet. 1995; 57: 1318-1324PubMed Google Scholar, 17Loudianos G. Dessi V. Lovicu M. Angius A. Figus A. Lilliu F. et al.Molecular characterization of Wilson disease in the Sardinian population - evidence of a founder effect.Hum Mutat. 1999; 14: 294-303Crossref PubMed Scopus (129) Google Scholar]. However, over half of all known mutations occur only rarely in any given population [9Petrukhin K. Fischer S.G. Pirastu M. Tanzi R.E. Chernov I. Devoto M. et al.Mapping, cloning and genetic characterization of the region containing the Wilson disease gene.Nat Genet. 1993; 5: 338-343Crossref PubMed Scopus (468) Google Scholar, 12Thomas G.R. Forbes J.R. Roberts E.A. Walshe J.M. Cox D.W. The Wilson disease gene: spectrum of mutations and their consequences.Nat Genet. 1995; 9: 210-217Crossref PubMed Scopus (487) Google Scholar, 13Shah A.B. Chernov I. Zang H.T. Ross B.M. Das K. Lutsenko S. et al.Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation and functional analyses.Am J Hum Gen. 1997; 61: 317-328Abstract Full Text PDF PubMed Scopus (302) Google Scholar, 14Loudianos G. Dessi V. Lovicu M. Angius A. Altuntas B. Giacchino R. et al.Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.J Med Genet. 1999; 36: 833-836PubMed Google Scholar, 15Loudianos G. Dessi V. Angius A. Lovicu M. Loi A. Deiana M. et al.Wilson disease mutations associated with uncommon haplotypes in Mediterranean patients.Hum Genet. 1996; 98: 640-642Crossref PubMed Scopus (40) Google Scholar, 16Figus A. Angius A. Loudianos G. Bertini C. Dessi V. Loi A. et al.Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.Am J Hum Genet. 1995; 57: 1318-1324PubMed Google Scholar, 18Loudianos G. Dessi V. Lovicu M. Angius A. Nurchi A. Sturniolo G.C. et al.Further delineation of the molecular pathology of Wilson disease in the Mediterranean population.Hum Mutat. 1998; 12: 89-94Crossref PubMed Scopus (79) Google Scholar, 19Loudianos G. Dessi V. Lovicu M. Angius A. Kanavakis E. Tzetis M. et al.Haplotype and mutation analysis in Greek patients with Wilson disease.Eur J Hum Genet. 1998; 6: 487-491Crossref PubMed Scopus (47) Google Scholar]. Most patients are compound heterozygotes, possessing alleles with two different mutations [12Thomas G.R. Forbes J.R. Roberts E.A. Walshe J.M. Cox D.W. The Wilson disease gene: spectrum of mutations and their consequences.Nat Genet. 1995; 9: 210-217Crossref PubMed Scopus (487) Google Scholar, 13Shah A.B. Chernov I. Zang H.T. Ross B.M. Das K. Lutsenko S. et al.Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation and functional analyses.Am J Hum Gen. 1997; 61: 317-328Abstract Full Text PDF PubMed Scopus (302) Google Scholar, 14Loudianos G. Dessi V. Lovicu M. Angius A. Altuntas B. Giacchino R. et al.Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations.J Med Genet. 1999; 36: 833-836PubMed Google Scholar, 15Loudianos G. Dessi V. Angius A. Lovicu M. Loi A. Deiana M. et al.Wilson disease mutations associated with uncommon haplotypes in Mediterranean patients.Hum Genet. 1996; 98: 640-642Crossref PubMed Scopus (40) Google Scholar, 16Figus A. Angius A. Loudianos G. Bertini C. Dessi V. Loi A. et al.Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations.Am J Hum Genet. 1995; 57: 1318-1324PubMed Google Scholar, 18Loudianos G. Dessi V. Lovicu M. Angius A. Nurchi A. Sturniolo G.C. et al.Further delineation of the molecular pathology of Wilson disease in the Mediterranean population.Hum Mutat. 1998; 12: 89-94Crossref PubMed Scopus (79) Google Scholar, 26Schilsky M.L. Identification of the Wilson's disease gene: clues for disease pathogenesis and the potential for molecular diagnosis.Hepatology. 1994; 20: 529-533Crossref PubMed Scopus (22) Google Scholar]. 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 [4Gollan J.L. Gollan T.J. Wilson diesease in 1998: genetic, diagnostic and therapeutic aspects.J Hepatol. 1998; 28: 28-36Abstract Full Text PDF PubMed Google Scholar, 8Bull P.C. Thomas G.R. Rommens J.M. Forbes J.R. Cox D.W. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.Nat Genet. 1993; 5: 327-337Crossref PubMed Scopus (1688) Google Scholar, 9Petrukhin K. Fischer S.G. Pirastu M. Tanzi R.E. Chernov I. Devoto M. et al.Mapping, cloning and genetic characterization of the region containing the Wilson disease gene.Nat Genet. 1993; 5: 338-343Crossref PubMed Scopus (468) Google Scholar, 10Tanzi R.E. Petrukhin K. Chernov I. Pellequer J.L. Wasco W. Ross B. et al.The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.Nat Genet. 1993; 5: 344-350Crossref PubMed Scopus (1174) Google Scholar, 11Terada K. Schilsky M.L. Miura N. Sugiyama T. ATP7B (WND) protein.Int J Biochem Cell Biol. 1998; 30: 1063-1067Crossref PubMed Scopus (70) Google Scholar, 27Forbes J.R. Hsi G. Cox D.W. Role of copper-binding domain in the copper transport function of ATP7B, the P-type ATPase defective in Wilson disease.J Biol Chem. 1999; 274: 12408-12413Crossref PubMed Scopus (143) Google Scholar]. Copper binding occurs via cysteine residues [28Lutsenko S. Petrukhin K. Cooper M.J. Gilliam C.T. Kaplan J.H. N-terminal domains of human copper-transporting adenosine triphosphatases (the Wilson's and Menkes disease proteins) bind copper selectively in vivo and in vitro with stoichiometry of one copper per metal-binding repeat.J Biol Chem. 1997; 272: 18939-18944Crossref PubMed Scopus (213) Google Scholar, 29Di Donato M. Narindrasorasak S. Forbes J.R. Cox D.W. Sarkar B. Expression, purification and metal binding properties of the N-terminal domain from the Wilson disease putative copper-transporting ATPase (ATP7B).J Biol Chem. 1997; 272: 33279-33282Crossref PubMed Scopus (139) Google Scholar] and may be co-operative, based on competitive zinc binding experiments [[29]Di Donato M. Narindrasorasak S. Forbes J.R. Cox D.W. Sarkar B. Expression, purification and metal binding properties of the N-terminal domain from the Wilson disease putative copper-transporting ATPase (ATP7B).J Biol Chem. 1997; 272: 33279-33282Crossref PubMed Scopus (139) Google Scholar]. The copper-binding domains of the ATP7B protein remove copper from cytosolic ligands and transport it within hepatocytes prior to its subsequent excretion [[30]Wu J. Forbes J.R. Chen H.S. Cox D.W. The L.E.C. rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene.Nat Genet. 1994; 7: 541-545Crossref PubMed Scopus (347) Google Scholar]. These domains may also function as copper sensors [29Di Donato M. Narindrasorasak S. Forbes J.R. Cox D.W. Sarkar B. Expression, purification and metal binding properties of the N-terminal domain from the Wilson disease putative copper-transporting ATPase (ATP7B).J Biol Chem. 1997; 272: 33279-33282Crossref PubMed Scopus (139) Google Scholar, 31Vulpe C. Levinson B. Whitney S. Packman S. Gitschier J. Isolation of a candidate for Menkes disease and evidence that it encodes a copper-transporting ATPase.Nat Genet. 1993; 3: 7-13Crossref PubMed Scopus (1208) Google Scholar, 32Petris M.J. Mercer J.F. Culvenor J.G. Lockhart P. Gleeson P.A. Camakaris J. Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking.EMBO J. 1996; 15: 6084-6089Crossref PubMed Scopus (528) Google Scholar]. In the hepatoblastoma-derived HepG2 cell line, the ATP7B protein is synthesised as a single 165 kDa protein localised to the trans-Golgi apparatus [33Hung I.H. Suzuki Y. Yamaguchi D.S. Yuans R.D. Klausner R.D. Gitlin J.D. Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae.J Biol Chem. 1997; 272: 21461-21466Crossref PubMed Scopus (287) Google Scholar, 34Yang X.L. Miura N. Kawarada Y. Terada K. Petrukhin K. Gilliam T.C. Sugiyama T. Two forms of Wilson disease protein produced by alternative splicing are localised in distinct cellular compartments.Biochem J. 1997; 326: 897-902Crossref PubMed Scopus (86) Google Scholar]. 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 [32Petris M.J. Mercer J.F. Culvenor J.G. Lockhart P. Gleeson P.A. Camakaris J. Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking.EMBO J. 1996; 15: 6084-6089Crossref PubMed Scopus (528) Google Scholar, 33Hung I.H. Suzuki Y. Yamaguchi D.S. Yuans R.D. Klausner R.D. Gitlin J.D. Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae.J Biol Chem. 1997; 272: 21461-21466Crossref PubMed Scopus (287) Google Scholar, 35Schaefer M. Hopkins R.G. Failla M.L. Gitlin J.D. Hepatocyte-specific localization and copper-dependent trafficking of the Wilson's disease protein in the liver.Am J Physiol. 1999; 276: G639-G646PubMed Google Scholar]. 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 [11Terada K. Schilsky M.L. Miura N. Sugiyama T. ATP7B (WND) protein.Int J Biochem Cell Biol. 1998; 30: 1063-1067Crossref PubMed Scopus (70) Google Scholar, 27Forbes J.R. Hsi G. Cox D.W. Role of copper-binding domain in the copper transport function of ATP7B, the P-type ATPase defective in Wilson disease.J Biol Chem. 1999; 274: 12408-12413Crossref PubMed Scopus (143) Google Scholar, 29Di Donato M. Narindrasorasak S. Forbes J.R. Cox D.W. Sarkar B. Expression, purification and metal binding properties of the N-terminal domain from the Wilson disease putative copper-transporting ATPase (ATP7B).J Biol Chem. 1997; 272: 33279-33282Crossref PubMed Scopus (139) Google Scholar]. 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 [36La Fontaine S. Firth S.D. Camakaris J. Englezou A. Theophilos M.B. Petris M.J. et al.Correction of the copper transport defect of Menkes patient fibroblasts by expression of the Menkes and Wilson ATPases.J Biol Chem. 1998; 273: 31375-31380Crossref PubMed Scopus (96) Google Scholar, 37Payne A.S. Kelly E.J. Gitlin J.D. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation.Proc Natl Acad Sci USA. 1998; 95: 10854-10859Crossref PubMed Scopus (185) Google Scholar].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]Forbes J.R. Hsi G. Cox D.W. Role of copper-binding domain in the copper transport function of ATP7B, the P-type ATPase defective in Wilson disease.J Biol Chem. 1999; 274: 12408-12413Crossref PubMed Scopus (143) Google Scholar]. 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]Lutsenko S. Cooper M.J. Localization of the Wilson's disease protein product to mitochondria.Proc Natl Acad Sci USA. 1998; 95: 6004-6009Crossref PubMed Scopus (125) Google Scholar]. 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 [4Gollan J.L. Gollan T.J. Wilson diesease in 1998: genetic, diagnostic and therapeutic aspects.J Hepatol. 1998; 28: 28-36Abstract Full Text PDF PubMed Google Scholar, 8Bull P.C. Thomas G.R. Rommens J.M. Forbes J.R. Cox D.W. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.Nat Genet. 1993; 5: 327-337Crossref PubMed Scopus (1688) Google Scholar, 10Tanzi R.E. Petrukhin K. Chernov I. Pellequer J.L. Wasco W. Ross B. et al.The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.Nat Genet. 1993; 5: 344-350Crossref PubMed Scopus (1174) Google Scholar, 35Schaefer M. Hopkins R.G. Failla M.L. Gitlin J.D. Hepatocyte-specific localization and copper-dependent trafficking of the Wilson's disease protein in the liver.Am J Physiol. 1999; 276: G639-G646PubMed Google Scholar, 39Petrukhin K. Lutsenko S. Chernov I. Ross B.H. Kaplan J.H. Gilliam T.C. Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions.Hum Mol Genet. 1994; 3: 1647-1656Crossref PubMed Scopus (301) Google Scholar, 40Yamaguchi Y.M. Heiny E. Gitlin J.D. Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease.Biochem Biophys Res Commun. 1993; 197: 271-277Crossref PubMed Scopus (473) Google Scholar]. 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]Saito T. Okabe M. Hosokawa T. Kurasaki M. Hata A. Endo F. et al.Immunohistochemical determination of the Wilson copper-transporting P-type ATPase in the brain tissues of the rat.Neurosci Lett. 1999; 266: 13-16Crossref PubMed Scopus (36) Google Scholar]. 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 [42Schilsky M.L. Scheinberg I.H. Sternlieb I. Liver transplantation for Wilson's disease: indications and outcome.Hepatology. 1994; 19: 583-587Crossref PubMed Scopus (248) Google Scholar, 43Polson R.J. Rolles K. Calne R.Y. Williams R. Marsden D. Reversal of severe neurological manifestations of Wilson's disease following orthotopic liver transplantation.Q J Med. 1987; 64: 685-691PubMed Google Scholar], with successful liver replacement presumably facilitating the mobilisation of copper from extrahepatic sites. Instances of resolution of Kayser–Fleischer rings in this setting [[42]Schilsky M.L. Scheinberg I.H. Sternlieb I. Liver transplantation for Wilson's disease: indications and outcome.Hepatology. 1994; 19: 583-587Crossref PubMed Scopus (248) Google Scholar] 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]Wilson S.A.K. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver.Brain. 1912; 34: 295-509Crossref Scopus (758) Google Scholar] 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 [4Gollan J.L. Gollan T.J. Wilson diesease in 1998: genetic, diagnostic and therapeutic aspects.J Hepatol. 1998; 28: 28-36Abstract Full Text PDF PubMed Google Scholar, 45Scheinberg I.H. Sternlieb I. Wilson's disease.in: Wright R. Millward-Sadler G.H. Alberti K.G. Liver and biliary disease. W.B. Saunders Co, London1985: 949-961Google Scholar, 46Walshe J.M. Wilson's disease presenting with features of hepatic dysfunction: a clinical analysis of eighty-seven patients.Q J Med. 1989; 70: 253-263PubMed Google Scholar, 47Sokol R.J. Wilson's disease and Indian childhood cirrhosis.in: Suchy F.J. Liver disease in children. Mosby, St. Louis1994: 747-772Google Scholar, 48Bonne-Tamir B. Frydman M. Agger M.S. Bekeer R. Bowcock A.M. Hebert J.M. et al.Wilson's disease in Israel: a genetic and epidemiological study.Ann Hum Genet. 1990; 54: 155-168Crossref PubMed Scopus (28) Google Scholar]. 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]Sternlieb I. Perspectives on Wilson's disease.Hepatology. 1990; 12: 1234-1239Crossref PubMed Scopus (195) Google Scholar]. The rate of progression from fatty infiltration to cirrhosis is variable, with no relation between age and likelihood of cirrhosis [[50]Gow P.J. Smallwood R.A. Angus P.W. Smith A.L. Wall A.J. Sewell R.B. Diagnosis of Wilson's disease: an experience over three decades.Gut. 2000; 46: 415-419Crossref PubMed Scopus (203) Google Scholar]. Wilson's disease may also present as fulminant hepatic failure, especially in females [42Schilsky M.L. Scheinberg I.H. Sternlieb I. 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