| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1999: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Background : Fulminant hepatic failure is rare but fatal manifestation of Wilson's disease (WD). Although many mutations of the gene WD (ATP7B) have been reported, genotype-phenotype correlation in WD was not completely investigated and specific mutations related to fulminant hepatic failure have not been found. Aims : In this study, we, detected mutations of ATP7B among Japanese patients with WD including patients with fulminant hepatic failure and sought the correlation between mutations and phenotypes. We also sought to determine if genotypic assignment according to the types of protein-product could be related to the prevalence of fulminant hepatic failureamong the patients with WD.Subjects : NDA was isolated from peripheral blood collected from 45 unrelated Japanese families including 51 patients with WD.Methods : 1) Each exon of ATP7B was amplified by PCR, and the products were screened by SSCP.When abnormal bans were detected by SSCP, patient DNA was directly sequenced to identi
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fy the mutations. 2) Out of patients we selected homozygotes and searched for correlations between each mutation and clinical manifestations and serum ceruloplasmin level. 3) We divided the genotypes into two groups according to their types of ATP7B product (Truncated group [T] : two truncated alleles including nonsense, insertion, deletion, and splice site mutation, Missense group [M] : one or two missense alleles). We also divided the phenotypes into two groups (Fulminant hepatic failure [F] and [non-F] group). To assess the relation between the prevalence of fulminant hepatic failure (FHF) and genotypic groups ([T] and [M]), we performed a fisher's exact test. Results : 1) We indetified 22 mutations in 49 patients with WD.At least one mutation was detected in 49 patients out of 43 WD families. 2) Eleven families were homozygous. Regarding each homozygote including more than two unrelated families, there was no correlation between mutation and phenotype. 3) Genetically 11 patients were assigned to [T] group and 31 to [M] group. Phenotypically, 4 patients were [F] group and 38 were [non-F] group. All patients in [F] group belong to [T] group. The prevalence of FHF in [T] group was 36.4% and significantly higher than in [M]. group (p<0.003). Conclusions : Although there was no correlation between each mutation and phenotypes, genotypic assignment according to the types of protein-product, truncated or not truncated, revealed that phenotypes for truncation of ATP7B were associated with high prevalence of hueminnt hepatic failure. Less
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