Journal of Inherited Metabolic Disease

, Volume 33, Supplement 3, pp 233–240 | Cite as

Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease

  • Karl Heinz WeissEmail author
  • Heiko Runz
  • Barbara Noe
  • Daniel Nils Gotthardt
  • Uta Merle
  • Peter Ferenci
  • Wolfgang Stremmel
  • Joachim Füllekrug
Research Report


Wilson disease (WD) is an autosomal-recessive copper overload disorder caused by mutations in the copper-transporting adenosine triphosphatase (ATPase) ATP7B. It presents with a highly variable clinical phenotype ranging from asymptomatic to fulminant hepatic failure or progressive neurological involvement. No clear genotype–phenotype correlation has been established. Thus, variants in modifier genes could have an impact on WD manifestation and severity. Recently, the antiapoptotic protein baculoviral IAP repeat-containing protein 4 BIRC4/XIAP has been suggested as a regulator of copper-induced cell death. With the aim of investigating a putative role of BIRC4/XIAP as modifier gene in individuals with copper overload, we analyzed a WD patient cohort (n = 98) for sequence variants at the BIRC4/XIAP locus. When compared with clinical data, the previously described coding single nucleotide polymorphisms (SNPs) at the BRIC4/XIAP locus (rs28382721, rs28382722, rs28382723, rs5956583, rs28382740, rs12838858, rs28382741) did not correlate with age of onset or clinical presentation in our collective. However, three previously unreported variants in the BIRC4/XIAP gene were identified (c.1-26 T > G; c.1408A > T; p.T470S; c.1019A > G; p.N340S). The two patients with variants leading to amino acid exchanges in the BIRC4/XIAP protein showed a remarkably early disease onset at the age of 5 years. Furthermore, one of these patients was only heterozygous for disease-causing mutations in the ATP7B gene. In summary, these data emphasize the need to further elucidate a role of BIRC4/XIAP variants as putative pathogenetic factors in copper overload disorders.


Wilson Disease Menkes Disease ATP7B Gene Intracellular Copper Copper Overload 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Wilson disease


Baculoviral IAP repeat-containing protein 4


X-linked inhibitor of apoptosis protein


Copper metabolism MURR1 domain


Single nucleotide polymorphism


Mouse U2af1-rs1 region


Not significant


Not determined



We sincerely thank the patients for their participation in this study. The authors thank Sabine Tuma for excellent technical assistance. This work was supported by a grant of the Dietmar Hopp Foundation (to WS), a Young Investigator Grant of the Medical Faculty of the University of Heidelberg (to KHW), and a grant by the Stiftung für Krebs-und Scharlachforschung (to KHW).

Supplementary material

10545_2010_9123_MOESM1_ESM.pdf (16 kb)
Suppl Table 1 Primer used for polymerase chain reaction (PCR) amplification and sequencing of BIRC4/XIAP (PDF 15 kb)


  1. Ala A et al (2005) Wilson disease in septuagenarian siblings: raising the bar for diagnosis. Hepatology 41(3):668–670PubMedCrossRefGoogle Scholar
  2. Ala A et al (2007) Wilson’s disease. Lancet 369(9559):397–408PubMedCrossRefGoogle Scholar
  3. Bull PC et al (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5(4):327–337PubMedCrossRefGoogle Scholar
  4. Burstein E et al (2004) A novel role for XIAP in copper homeostasis through regulation of MURR1. EMBO J 23(1):244–254PubMedCrossRefGoogle Scholar
  5. Coronado VA et al (2005) COMMD1 (MURR1) as a candidate in patients with copper storage disease of undefined etiology. Clin Genet 68(6):548–551PubMedCrossRefGoogle Scholar
  6. de Bie P et al (2005) The many faces of the copper metabolism protein MURR1/COMMD1. J Hered 96(7):803–811PubMedCrossRefGoogle Scholar
  7. El-Serag HB, White DL, Mitra N (2008) Genetic association studies: from “searching under the lamppost” to “fishing in the pond”. Gastroenterology 134(3):662–664PubMedCrossRefGoogle Scholar
  8. Ferenci P et al (2003) Diagnosis and phenotypic classification of Wilson disease. Liver Int 23(3):139–142PubMedCrossRefGoogle Scholar
  9. Ferenci P et al (2007) Late-onset Wilson’s disease. Gastroenterology 132(4):1294–1298PubMedCrossRefGoogle Scholar
  10. Gitlin JD (2003) Wilson disease. Gastroenterology 125(6):1868–1877PubMedCrossRefGoogle Scholar
  11. Gotthardt D et al (2008) A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Hepatology 48(4):1157–1166PubMedCrossRefGoogle Scholar
  12. Gromadzka G et al (2006) p.H1069Q mutation in ATP7B and biochemical parameters of copper metabolism and clinical manifestation of Wilson’s disease. Mov Disord 21(2):245–248PubMedCrossRefGoogle Scholar
  13. Harris ED (2000) Cellular copper transport and metabolism. Annu Rev Nutr 20:291–310PubMedCrossRefGoogle Scholar
  14. Ioannidis JP, Trikalinos TA, Khoury MJ (2006) Implications of small effect sizes of individual genetic variants on the design and interpretation of genetic association studies of complex diseases. Am J Epidemiol 164(7):609–614PubMedCrossRefGoogle Scholar
  15. Klomp AE et al (2003) The ubiquitously expressed MURR1 protein is absent in canine copper toxicosis. J Hepatol 39(5):703–709PubMedCrossRefGoogle Scholar
  16. Lovicu M et al (2006) The canine copper toxicosis gene MURR1 is not implicated in the pathogenesis of Wilson disease. J Gastroenterol 41(6):582–587PubMedCrossRefGoogle Scholar
  17. Maine GN et al (2009) COMMD1 expression is controlled by critical residues that determine XIAP binding. Biochem J 417(2):601–609PubMedCrossRefGoogle Scholar
  18. Merle U et al (2007) Clinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study. Gut 56(1):115–120PubMedCrossRefGoogle Scholar
  19. Mufti AR et al (2006) XIAP Is a copper binding protein deregulated in Wilson’s disease and other copper toxicosis disorders. Mol Cell 21(6):775–785PubMedCrossRefGoogle Scholar
  20. Mufti AR, Burstein E, Duckett CS (2007) XIAP: cell death regulation meets copper homeostasis. Arch Biochem Biophys 463(2):168–174PubMedCrossRefGoogle Scholar
  21. Nicastro E et al (2009) Genotype-phenotype correlation in Italian children with Wilson’s disease. J Hepatol 50(3):555–561PubMedCrossRefGoogle Scholar
  22. Ng PC, Henikoff S (2002) Accounting for human polymorphisms predicted to affect protein function. Genome Res 12(3):436–446PubMedCrossRefGoogle Scholar
  23. Panagiotakaki E et al (2004) Genotype-phenotype correlations for a wide spectrum of mutations in the Wilson disease gene (ATP7B). Am J Med Genet A 131(2):168–173PubMedCrossRefGoogle Scholar
  24. Prohaska JR (2008) Role of copper transporters in copper homeostasis. Am J Clin Nutr 88(3):826S–829SPubMedGoogle Scholar
  25. Prohaska JR, Gybina AA (2004) Intracellular copper transport in mammals. J Nutr 134(5):1003–1006PubMedGoogle Scholar
  26. Rigaud S et al (2006) XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444(7115):110–114PubMedCrossRefGoogle Scholar
  27. Riordan SM, Williams R (2001) The Wilson’s disease gene and phenotypic diversity. J Hepatol 34(1):165–171PubMedCrossRefGoogle Scholar
  28. Roberts EA, Schilsky ML (2003) A practice guideline on Wilson disease. Hepatology 37(6):1475–1492PubMedCrossRefGoogle Scholar
  29. Roberts EA, Schilsky ML (2008) Diagnosis and treatment of Wilson disease: an update. Hepatology 47(6):2089–2111PubMedCrossRefGoogle Scholar
  30. Salzer U et al (2008) Sequence analysis of BIRC4/XIAP in male patients with common variable immunodeficiency. Int Arch Allergy Immunol 147(2):147–151PubMedCrossRefGoogle Scholar
  31. Serre D et al (2008) Differential allelic expression in the human genome: a robust approach to identify genetic and epigenetic cis-acting mechanisms regulating gene expression. PLoS Genet 4(2):e1000006PubMedCrossRefGoogle Scholar
  32. Shah AB 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(2):317–328PubMedCrossRefGoogle Scholar
  33. Spee B et al (2007) Functional consequences of RNA interference targeting COMMD1 in a canine hepatic cell line in relation to copper toxicosis. Anim Genet 38(2):168–170PubMedCrossRefGoogle Scholar
  34. Stapelbroek JM et al (2004) The H1069Q mutation in ATP7B is associated with late and neurologic presentation in Wilson disease: results of a meta-analysis. J Hepatol 41(5):758–763PubMedCrossRefGoogle Scholar
  35. Steindl P et al (1997) Wilson’s disease in patients presenting with liver disease: a diagnostic challenge. Gastroenterology 113(1):212–218PubMedCrossRefGoogle Scholar
  36. Stuehler B et al (2004) Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients. J Mol Med 82(9):629–634PubMedCrossRefGoogle Scholar
  37. Tanzi RE et al (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5(4):344–350PubMedCrossRefGoogle Scholar
  38. Tao TY et al (2003) The copper toxicosis gene product Murr1 directly interacts with the Wilson disease protein. J Biol Chem 278(43):41593–41596PubMedCrossRefGoogle Scholar
  39. The International HapMap Project (2003) Nature 426(6968):789–796CrossRefGoogle Scholar
  40. Twedt DC, Sternlieb I, Gilbertson SR (1979) Clinical, morphologic, and chemical studies on copper toxicosis of Bedlington Terriers. J Am Vet Med Assoc 175(3):269–275PubMedGoogle Scholar
  41. van De Sluis B et al (2002) Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Hum Mol Genet 11(2):165–173CrossRefGoogle Scholar
  42. Weiss KH et al (2006) Copper toxicosis gene MURR1 is not changed in Wilson disease patients with normal blood ceruloplasmin levels. World J Gastroenterol 12(14):2239–2242PubMedGoogle Scholar
  43. Weiss KH et al (2008) Copper-induced translocation of the Wilson disease protein ATP7B independent of Murr1/COMMD1 and Rab7. Am J Pathol 173(6):1783–1794PubMedCrossRefGoogle Scholar
  44. Wijmenga C, Klomp LW (2004) Molecular regulation of copper excretion in the liver. Proc Nutr Soc 63(1):31–39PubMedCrossRefGoogle Scholar
  45. Wu ZY et al (2006) Mutation analysis of 218 Chinese patients with Wilson disease revealed no correlation between the canine copper toxicosis gene MURR1 and Wilson disease. J Mol Med 84(5):438–442PubMedCrossRefGoogle Scholar
  46. Yue P, Melamud E, Moult J (2006) SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinform 7:166CrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Karl Heinz Weiss
    • 1
    Email author
  • Heiko Runz
    • 2
  • Barbara Noe
    • 1
  • Daniel Nils Gotthardt
    • 1
  • Uta Merle
    • 1
  • Peter Ferenci
    • 3
  • Wolfgang Stremmel
    • 1
  • Joachim Füllekrug
    • 1
  1. 1.Department of GastroenterologyUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Institute of Human GeneticsUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Department of GastroenterologyUniversity Hospital ViennaViennaAustria

Personalised recommendations