A New Type of Defect in the Gene for Bilirubin Uridine 5 '-Diphosphate-Glucuronosyltransferase in a Patient with Crigler-Najjar Syndrome Type I

Aono, Sachiko; Yamada, Yasukazu; Keino, Hiroomi; Sasaoka, Y.; Nakagawa, Tsuneo; Onishi, Shoju; Mimura, Satoshi; Koiwai, Osamu; Sato, Hiroshi

doi:10.1203/00006450-199406000-00002

Cited by 70 publications

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References 22 publications

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“…By screening, we found four patients who suffered from CN-I in Japan. We already reported that one of them, patient A, carried a homozygous nonsense mutation in exon 1 of the gene for bilirubin U G T (Aono et al, 1994). We have now analyzed the genetic backgrounds of the other three patients, B, C, and D, and, as we report herein, all three patients have a mutation in exon 1 identical to that found in patient A.…”

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confidence: 52%

“…Unexpectedly, we found a mutation from C to A at position 840 (Fig. 1), which was identical to the mutation in patient A (Aono et al, 1994). Next we analyzed the DNA sequence of the gene for bilirubin UGT of patient D.…”

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confidence: 56%

“…Patient C was an elder sister of patient B. The entire first to fifth exons of the gene for bilirubin UGT of the patients and normal controls were amplified by PCR with specific primers (Aono et al, 1994) It is not clear which child (G or H) was produced by E and F. A cross indicates that a child died at birth. Vol.…”

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Three Japanese patients with Crigler-Najjar syndrome type I carry an identical nonsense mutation in the gene for UDP-glucuronosyltransferase

et al. 1995

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Three Japanese patients with Crigler-Najjar syndrome type I carry an identical nonsense mutation in the gene for UDP-glucuronosyltransferase

et al. 1995

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“…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%

“…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. Direct sequencing was performed three times for each patient as previously described (Aono et al 1994). …”

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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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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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Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: Correlation of genotype to phenotype

et al. 2000

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Uridine‐diphosphoglucuronate glucuronosyltransferases (UGTs) are a family of enzymes that conjugate various endogenous and exogenous compounds with glucuronic acid and facilitate their excretion in the bile. Bilirubin‐UGT1 (UGT1A1) is the only isoform that significantly contributes to the conjugation of bilirubin. Lesions in the gene encoding bilirubin‐UGT1, lead to complete or partial inactivation of the enzyme causing the rare autosomal recessively inherited conditions, Crigler‐Najjar syndrome type‐1 (CN‐1) and type 2 (CN‐2), respectively. Inactivation of the enzyme leads to accumulation of unconjugated bilirubin in the serum. Severe hyperbilirubinemia seen in CN‐1 can cause bilirubin encephalopathy (kernicterus). Kernicterus can be fatal or may leave behind permanent neurological sequelae. Here, we have compiled more than 50 genetic lesions of UGT1A1 that cause CN‐1 (including 9 novel mutations) or CN‐2 (including 3 novel mutations) and have presented a correlation of structure to function of UGT1A1. In contrast to Crigler‐Najjar syndromes, Gilbert syndrome is a common inherited condition characterized by mild hyperbilirubinemia. An insertional mutation of the TATAA element upstream to UGT1A1 results in a reduced level of expression of the gene. Homozygosity for the variant promoter is required for Gilbert syndrome, but not sufficient for manifestation of hyperbilirubinemia, which is partly dependent on the rate of bilirubin production. Several structural mutations of UGT1A1, for example, a G71R substitution, have been reported to cause mild reduction of UGT activity toward bilirubin, resulting in mild hyperbilirubinemia, consistent with Gilbert syndrome. When the normal allele of a heterozygote carrier for a Crigler‐Najjar type structural mutation contains a Gilbert type promoter, intermediate levels of hyperbilirubinemia, consistent with the diagnosis of CN‐2, may be observed. Hum Mutat 16:297–306, 2000. © 2000 Wiley‐Liss, Inc.

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A New Type of Defect in the Gene for Bilirubin Uridine 5 '-Diphosphate-Glucuronosyltransferase in a Patient with Crigler-Najjar Syndrome Type I

Cited by 70 publications

References 22 publications

Three Japanese patients with Crigler-Najjar syndrome type I carry an identical nonsense mutation in the gene for UDP-glucuronosyltransferase

Three Japanese patients with Crigler-Najjar syndrome type I carry an identical nonsense mutation in the gene for UDP-glucuronosyltransferase

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

Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: Correlation of genotype to phenotype

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