Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease.
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.
Weiss
Karl Heinz
KH
Department of Gastroenterology, University Hospital Heidelberg, INF 410, 69120 Heidelberg, Germany. Karl-heinz_weiss@med.uni-heidelberg.de
Runz
Heiko
H
Noe
Barbara
B
Gotthardt
Daniel Nils
DN
Merle
Uta
U
Ferenci
Peter
P
Stremmel
Wolfgang
W
Füllekrug
Joachim
J
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D027682:Cation Transport Proteins / Q000235:genetics*; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D060045:Genes, Modifier; D020022:Genetic Predisposition to Disease; D006527:Hepatolenticular Degeneration / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics*; D055815:Young Adult
D027682:Cation Transport Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases