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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

Abstract

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.

Keywords

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.

Abbreviations

WD

Wilson disease

BIRC4

Baculoviral IAP repeat-containing protein 4

XIAP

X-linked inhibitor of apoptosis protein

COMMD

Copper metabolism MURR1 domain

SNP

Single nucleotide polymorphism

Murr1

Mouse U2af1-rs1 region

n.s.

Not significant

n.d.

Not determined

Notes

Acknowledgments

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)

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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

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