Human Genetics

, Volume 120, Issue 2, pp 151–159

Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing

Review

Abstract

Wilson disease is an autosomal recessive inherited disorder of copper metabolism. The Wilson disease gene codes for a copper transporting P-type ATPase (ATP7B). Molecular genetic analysis reveals at least 300 distinct mutations. While most reported mutations occur in single families, a few are more common. The most common mutation in patients from Central, Eastern, and Northern Europe is the point mutation H1069Q (exon 14). About 50–80% of Wilson disease (WD) patients from these countries carry at least one allele with this mutation with an allele frequency ranging between 30 and 70%. Other common mutations in Central and Eastern Europe are located on exon 8 (2299insC, G710S), exon 15 (3400delC) and exon 13 (R969Q). The allele frequency of these mutations is lower than 10%. In Mediterranean countries there is a wide range of mutations, the frequency of each of them varies considerably from country to country. In Sardinia, a unique deletion in the 5′ UTR (−441/−427 del) is very frequent. In mainland Spain the missense mutation M645R in exon 6 is particularly common. Data from non-European countries are scarce. Most data from Asia are from Far Eastern areas (China, South Korea and Japan) where the R778L missense mutation in exon 8 is found with an allele frequency of 14–49%. In summary, given the constant improvement of analytic tools genetic testing will become an integral part for the diagnosis of WD. Knowledge of the differences in the worldwide distribution of particular mutations will help to design shortcuts for genetic diagnosis of WD.

References

  1. Al Jumah M, Majumdar R, Al Rajeh S, Awada A, Al Zaben A, Al Traif I et al (2004) clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudi-specific mutations. Eur J Neurol 11:121–124PubMedCrossRefGoogle Scholar
  2. Bachmann H, Lössner J, Kühn HJ, Siegemund R (1991) Occurrence, genetics and epidemiology of Wilson’s disease in east Germany. In: Czlonkowska A, van der Hamer CJA (eds) Proceedings of the 5th international symposium on Wilson's disease. Technical University Delft, pp 121–128Google Scholar
  3. Caca K, Ferenci P, Kuhn HJ, Polli C, Willgerodt H, Kunath B et al (2001) High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis. J Hepatol 35:575–581PubMedCrossRefGoogle Scholar
  4. Cater MA, Forbes J, La Fontaine S, Cox D, Mercer JFB (2004) Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites. Biochem J 380:805–813PubMedCrossRefGoogle Scholar
  5. Curtis D, Durkie M, Balac P, Sheard D, Goodeve A. Peake I, Quarrell O, Tanner S. (1999) A study of Wilson disease mutations in Britain. Hum Mutat 14:304–311PubMedCrossRefGoogle Scholar
  6. DiDonato M, Hsu HF, Narindrasorasak S, Que L Jr, Sarkar B (2000) Copper-induced conformational changes in the N-terminal domain of the Wilson disease copper-transporting ATPase. Biochemistry 39:1890–1896PubMedCrossRefGoogle Scholar
  7. Deguti MM, Genschel J, Cancado EL, Barbosa ER, Bochow B, Mucenic M, Porta G, Lochs H, Carrilho FJ, Schmidt HH (2004) Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat 398:1–8Google Scholar
  8. Ferenci P (2005a) Wilson’s disease (clinical genomics). Clin Gastroenterol Hepatol 3:726–733CrossRefGoogle Scholar
  9. Ferenci P (2005b) Wilson’s disease. In: Bacon B, O’Grady JG, DiBisceglie A, Lake JR (eds) Comprehensive clinical hepatology, chap 24. Elsevier, Mosby, pp 351–367Google Scholar
  10. Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I, Schilsky M, Cox D, Berr F (2003). Diagnosis and phenotypic classification of Wilson disease. Final report of the proceedings of the working party at the 8th international meeting on Wilson disease and Menkes disease, Leipzig/Germany, 2001. Liver Int 23:139–142PubMedCrossRefGoogle Scholar
  11. Ferenci P, Steindl-Munda P, Vogel W, Jessner W, Gschwantler M, Stauber R et al (2005a). Diagnostic value of quantitative hepatic copper determination in patients with Wilson disease. Clin Gastroenterol Hepatol 3:811–818CrossRefGoogle Scholar
  12. Ferenci P, Merle U, Folhoffer A, Evstatiev R, Yurdaydin C, Bruha R et al (2005b) Phenotype–genotype correlations in Wilson Disease (WD)—results of a multinational study. Hepatology 42(Suppl 1):258AGoogle Scholar
  13. Figus A, Angius A, Loudianos O, Bertini C; Dessi V, Loi A et al (1995) Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations. Am J Hum Genet 57:1318–1324PubMedGoogle Scholar
  14. Firneisz G, Lakatos PL, Szalay F, Polli C, Glant TT, Ferenci P (2002) Common mutations of ATP7B in Wilson disease patients from Hungary. Am J Med Genet 108:23–28PubMedCrossRefGoogle Scholar
  15. Garcia-Villareal L, Daniels S, Shaw SH, Cotton D, Galvin M, Geskes J 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 32:1329–1336CrossRefGoogle Scholar
  16. Gromadzka G, Schmidt HH, Genschel J, Bochow B, Rodo M, Tarnacka B, Litwin T, Chabik G, Clzonkowska A (2005) Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson’s disease. Clin Genet 68:524–532PubMedCrossRefGoogle Scholar
  17. Gu YH, Kodama H, Du SL, Gu QJ, Sun HJ, Ushijima H. (2003) Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson’s disease. Clin Genet 64:479–484PubMedCrossRefGoogle Scholar
  18. Gupta A, Aikath D, Neogi R, Datta S, Basu K, Mity B et al (2005) Molecular pathogenesis of Wilson disease: haplotype analysis, detection of prevalent mutations and genotype-phenotype correlation in Indian patients. Hum Genet 118:49–57PubMedCrossRefGoogle Scholar
  19. Huster D, Weizenegger M, Kress S et al (2004) Rapid detection of mutations in Wilson disease gene ATP7B by DNA strip technology. Clin Chem Lab Med 42:507–510PubMedCrossRefGoogle Scholar
  20. Ivanova-Smolenskaya IA, Ovchinnikov IV, Karabanov AV, Deineko NL, Poleshchuk VV, Markova ED, Illarioshkin SN (1999) The His1069Gln mutation in the ATP7B gene in Russian patients with Wilson disease. J Med Genet 36:174PubMedGoogle Scholar
  21. Kim EK, Yoo OJ, Song KY, Yoo HW, Choi SY, Cho SW et al (1998) Identification of three novel mutations and a high frequency of the Arg778Leu mutation in Korean patients with Wilson disease. Hum Mutat 11:275–278PubMedCrossRefGoogle Scholar
  22. Kumar S, Thapa BR, Kaur G, Prasad R (2005) Identification and molecular characterization of 18 novel mutations in the ATP7B gene from Indian Wilson disease patients: genotype. Clin Genet 67:443–445PubMedCrossRefGoogle Scholar
  23. Liu XQ, Zhang YF, Liu TT, Hsiao KJ, Zhang JM, Gu XF et al (2004) Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease. World J Gastroenterol 10:590–593PubMedGoogle Scholar
  24. Loudianos G, Dessi V, Lovicu M, Angius A, Nurchi A, Sturniolo GC et al (1998) Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat 12:89–94PubMedCrossRefGoogle Scholar
  25. Loudianos G, Dessi V, Lovicu M, Angius A, Altuntas B, Giacchino R et al (1999a) Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations. J Med Genet 36:833–836Google Scholar
  26. Loudianos G, Dessi V, Lovicu M, Angius A, Figus AL, Lilliu F et al (1999b) Molecular characterization of Wilson disease in the Sardinian population—evidence of a founder effect. Hum Mutat 14:294–303CrossRefGoogle Scholar
  27. Loudianos G, Kostic V, Solinas P, Lovicu M, Dessi V, Svetel M, Major T, Cao A (2003) Characterization of the molecular defect in the ATP7B gene in Wilson disease patients from Yugoslavia. Genet Test 7:107–112PubMedCrossRefGoogle Scholar
  28. Lovicu M, Dessi V, Zappu A et al (2003) Efficient strategy for molecular diagnosis of Wilson disease in the Sardinian population. Clin Chem 49:496–498PubMedCrossRefGoogle Scholar
  29. Margarit E, Bach V, Gomez D, Bruguera M, Jara P, Queralt R, Ballesta F (2005) Mutation analysis of Wilson disease in the Spanish population—identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet 68:61–68PubMedCrossRefGoogle Scholar
  30. Maier-Dobersberger Th, Rack S, Granditsch G, Korninger L, Steindl P, Mannhalter Ch, Ferenci P (1995) Diagnosis of Wilson’s disease in an asymptomatic sibling by DNA linkage analysis. Gastroenterology 109:2015–2018PubMedCrossRefGoogle Scholar
  31. Maier-Dobersberger T, Ferenci P, Polli C, Balac P, Dienes HP, Kaserer K et al (1997) Detection of the His1069Gln mutation in WD by rapid polymerase chain reaction. Ann Intern Med 127:21–26PubMedGoogle Scholar
  32. Morgan CT, Tsivkovskii R, Kosinsky YA, Efremov RG, Lutsenko S (2004) The distinct functional properties of the nucleotide-binding domain of ATP7B, the human copper-transporting ATPase. Analysis of the Wilson disease mutations E1064A, H1069Q, R1151H, and C1104F. J Biol Chem 279:36363–36371PubMedCrossRefGoogle Scholar
  33. Okada T, Shiono Y, Hayashi H, Satoh H, Sawada T, Suzuki A et al (2000) Mutational analysis of ATP7B and genotype–phenotype correlation in Japanese with Wilson’s disease. Hum Mutat 15:454–462PubMedCrossRefGoogle Scholar
  34. Olivarez L, Caggana M, Pass KA, Ferguson P, Brewer GJ (2001) Estimate of the frequency of Wilson’s disease in the US Caucasian population: a mutation analysis approach. Ann Hum Genet 65:459–463PubMedCrossRefGoogle Scholar
  35. Panagiotakaki E, Tzetis M, Manolaki N, Loudianos G, Papatheodorou A, Manesis E et al (2004) Genotype–phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet 131:168–173 CrossRefPubMedGoogle Scholar
  36. Petrukhin K, Fischer SG, Pirastu M, Tanzi RE, Chernov I, Devoto M et al (1993) Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat Genet 5:338–343PubMedCrossRefGoogle Scholar
  37. Petrukhin KE, Lutsenko S, Chernov I, Ross BM, Kaplan JH, Gilliam TC (1994) Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions. Hum Mol Genet 3:1647–1656PubMedCrossRefGoogle Scholar
  38. Reilly M, Daly L, Hutchinson M (1993) An epidemiological study of Wilson’s disease in the Republic of Ireland. J Neurol Neurosurg Psychiatr 56:298–300PubMedCrossRefGoogle Scholar
  39. Scheinberg IH, Sternlieb I (1984) Wilson’s disease, vol 23. Major problems in internal medicine. Saunders, PhiladelphiaGoogle Scholar
  40. Shah AB, Chernov I, Zjang HT, Ross B, Das K et al (1997) Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies. Genotype–phenotype correlation, and functional analyses. Am J Hum Genet 61:317–328PubMedCrossRefGoogle Scholar
  41. Shimizu N, Kawase C, Nakazono H, Hemmi H, Shimatake H, Aoki T (1995) A novel RNA splicing mutation in Japanese patients with Wilson disease. Biochem Biophys Res Commun 217:16–20PubMedCrossRefGoogle Scholar
  42. Steindl P, Ferenci P, Dienes HP, Grimm G, Pabinger I, Madl Ch et al (1997) Wilson’s disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 113:212–218PubMedCrossRefGoogle Scholar
  43. Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B et al (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5:344–350PubMedCrossRefGoogle Scholar
  44. Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW (1995) The WD gene: spectrum of mutations and their consequences. Nat Genet 9:210–217PubMedCrossRefGoogle Scholar
  45. Todorov T, Savov A, Jelev H, Panteleeva E, Konstantinova D, Krustev Z et al (2005) Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. Clin Genet 68:474–476PubMedCrossRefGoogle Scholar
  46. Vanderwerf SM, Cooper MJ, Stetsenko IV, Lutsenko S (2001) Copper specifically regulates intracellular phosphorylation of the Wilson’s disease protein, a human copper-transporting ATPase. J Biol Chem 276:36289–36294PubMedCrossRefGoogle Scholar
  47. Vrabelova S, Letocha O, Borsky M, Kozak L (2005) Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Genet Metab 86:277–285CrossRefGoogle Scholar
  48. Weirich G, Cabras AD, Serra S, Coni P, Nurcho AM, Faa G, Höfler H. (2002) Rapid identification of Wilson’s disease carriers by denaturing High-performance liquid chromatography. Prev Med 35:278–284PubMedCrossRefGoogle Scholar
  49. Wu Z, Wang N, Murong S, Lin M (2000) Identification and analysis of mutations of the Wilson disease gene in Chinese population. Chin Med J (Engl) 113:40–43Google Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  1. 1.Departments of Internal Medicine IV, Gastroenterology and HepatologyUniversity of ViennaViennaAustria

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