Predicted homozygous mis-sense mutation in Gilbert's syndrome

Soeda, Yoko; Yamamoto, Kazuo; Adachi, Yukihiko; Hori, Takeshi; Aono, Sachiko; Koiwai, Osamu; Sato, Hiroshi

doi:10.1016/s0140-6736(95)92514-7

Cited by 35 publications

(28 citation statements)

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“…We could not clearly indicate which mutation contributed to the phenotype as CN type II in the previous report. However, following that study, we found a patient with Gilbert's syndrome who was a single homozygote for Gly71Arg (Soeda et al 1995). Furthermore, double homozygotes for Gly71Arg and Tyr486Asp always express the phenotype of CN type II, so both of these homozygous missense mutations would additionally contribute to elevation of serum bilirubin concentration to the level found in CN type II.…”

Section: Discussionmentioning

confidence: 82%

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Analysis of bilirubin uridine 5′-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler-Najjar syndrome type II

et al. 1998

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Crigler-Najjar syndrome (CN) type II is caused by a reduction in hepatic bilirubin uridine 5Ј-diphosphate (UDP)-glucuronosyltransferase activity. Recently, there has been progress in mutation analysis of patients with CN type II. Here, we analyzed both the coding and the promoter regions of the gene in seven Japanese patients with CN type II from five unrelated families. The mutations found in this study were classified into three types. The first type was composed of double homozygous missense mutations (Gly71Arg and Tyr486Asp) in exons 1 and 5. These mutations, which were detected in five patients from three unrelated families, were the commonest. The second type, which was detected in one patient, consisted of a single homozygous missense mutation (Arg209Trp) in exon 1. The third type, which was detected in one patient and was a new type of mutation combination, was composed of a homozygous insertion mutation of the TATAA element and a heterozygous missense mutation (Pro229Gln) in exon 1. Although the first and the second type of mutations are recessive, the third type appears to be dominant with incomplete penetrance, since the allele frequency of the insertion mutation of the TATAA element is very high (40%).

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Section: Discussionmentioning

confidence: 82%

“…The promoter and coding regions of the UGT1*1 gene were amplified as described elsewhere (Aono et al 1994;Soeda et al 1995). Sense and anti-sense primers used for PCR to amplify the TATAA element of the gene were 5Ј-GCCATA-TATATATATATA-3Ј and 5Ј-GCTTGCTCAG-CATATATCTGGG-3Ј.…”

Section: Patients and Samplesmentioning

confidence: 99%

Analysis of bilirubin uridine 5′-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler-Najjar syndrome type II

et al. 1998

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“…Arrows highlight variants previously shown to be associated with human-health phenotypes in either multiple human subject studies or in individual association studies involving more than 100 human subjects; these include the UGT1A8*2 allele, 70,71 the three non-synonymous coding SNPs in UGT1A7 (*2,*3,*10), 69,72,73,81,82 two nsSNPs in UGT1A6 (*2,*3), 67,68,70 rs887829 -the SNP revealing the strongest association with tranilast-induced hyperbilirubinemia, 28 and the UGT1A1*6 allele. 10,24,25,[50][51][52][53][54][55][56][57][83][84][85][86][87] Figure 4 Two-point LD maps for variants of UGT1A1, UGT1A6, and UGT1A9 mapped by population. The patterns of pairwise LD, summarized by |D 0 |, include 60 variants in African-Americans (left), 52 in European-Americans (center), and 49 in Asians (right).…”

Section: Prediction Of Functional Effects Of Amino-acid Replacement Vmentioning

confidence: 99%

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

et al. 2005

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Common polymorphisms within the human UGT1A gene locus are associated with irinotecan and tranilast toxicity. To uncover additional functional variation across this gene cluster, cross-species sequence comparisons were performed. Evolutionarily conserved segments (a total of 47.1 kb) were re-sequenced in 24 African-American, 24 European-American, and 24 Asian individuals, and 381 segregating sites (including 123 singletons) were identified. Highly conserved coding sites were less likely to be polymorphic than diverged sites (Po0.0001) but this pattern was not observed at noncoding sites (P ¼ 0.1025). Among coding variants, the distribution of those computationally predicted to affect function was skewed toward low frequencies. Some alleles occurred at similar frequencies in each population; others had wide disparities. Although strong linkage disequilibrium was detected among the hepatically expressed genes, the degree of linkage disequilibrium varied among populations. These results suggest that rare functional gene variants and inter-population variability must be considered in the interpretation of association studies between UGT1A and drug metabolism/toxicity phenotypes.

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“…18 The frequency of the (TA) 7 allele is 30-40% in Caucasians, 13,15,17,19 while it is less frequent in the Japanese population, with the frequency being approximately 16%. 20,21 It was suggested that the GLY71Arg polymorphism may contribute to Gilbert's syndrome, particularly in Japanese and Asian patients. 14,22,23 Given these data, we set out to investigate the possible association of both the TA repeat and the GLY71Arg polymorphisms within UGT1A1, with hyperbilirubinemia observed during repeat dosing with tranilast in the PRESTO cohort.…”

Section: Introductionmentioning

confidence: 99%

A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia

Chen

et al. 2003

Pharmacogenomics J

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Tranilast (N-(3 0 4 0 -demethoxycinnamoyl)-anthranilic acid (N-5)) is an investigational drug for the prevention of restenosis following percutaneous transluminal coronary revascularization. An increase in bilirubin levels was observed in 12% of patients upon administration of tranilast in a phase III clinical trial. To identify the potential genetic factors that may account for the drug-induced hyperbilirubinemia, we examined polymorphisms in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in over a thousand patients. Our results suggested that the TA repeat polymorphism in UGT1A1, which predisposes some individuals to Gilbert's syndrome, predicted the susceptibility to tranilast-induced hyperbilirubinemia. The (TA) 7 /(TA) 7 genotype was present in 39% of the 127 hyperbilirubinemic patients vs 7% of the 909 controls (P ¼ 2 Â 10 À22 ). Rapid identification of genetic factors accounting for the observed adverse effect during the course of a double-blind clinical trial demonstrated the potential application of pharmacogenetics in the clinical development of safe and effective medicines.

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Predicted homozygous mis-sense mutation in Gilbert's syndrome

Cited by 35 publications

References 5 publications

Analysis of bilirubin uridine 5′-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler-Najjar syndrome type II

Analysis of bilirubin uridine 5′-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler-Najjar syndrome type II

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia

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