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Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease
Author(s) -
Weiss Karl Heinz,
Runz Heiko,
Noe Barbara,
Gotthardt Daniel Nils,
Merle Uta,
Ferenci Peter,
Stremmel Wolfgang,
Füllekrug Joachim
Publication year - 2010
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-010-9123-5
Subject(s) - xiap , inhibitor of apoptosis , biology , genetics , locus (genetics) , gene , allele , single nucleotide polymorphism , genotype , phenotype , cancer research , apoptosis , programmed cell death , caspase
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.