Crigler-Najjar syndrome type II is inherited both as a dominant and as a recessive trait

Koiwai, Osamu; Aono, Sachiko; Adachi, Yukihiko; Kamisako, Toshinori; Yasui, Yoshihiro; Nishizawa, Miwako; Sato, Hiroshi

doi:10.1093/hmg/5.5.645

Cited by 63 publications

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“…Gene analyses have shown both patients having recessive traits with homozygous missense mutations and a patient having dominant traits with a heterozygous nonsense mutation (Aono et al 1993;Bosma et al 1993;Koiwai et al 1996). In our study, inheritance in patients 2-7 was recessive, in agreement with findings reported earlier; however, patient 1 appears to show complicated inheritance.…”

Section: Discussionsupporting

confidence: 92%

“…In recent studies on mutation analysis of patients with CN type II, five types of mutations which exist exclusively in the coding region have been reported: a single homozygous missense mutation (Arg209Trp) (Bosma et al 1993), a single homozygous missense mutation (Gln331Arg) (Moghrabi et al 1993), double homozygous missense mutations (Gly71Arg and Tyr486Asp) (Aono et al 1993), heterozygous missense (Leu175Glu) and frame shift mutations (Seppen et al 1994), and a single heterozygous nonsense mutation (Gln331Stop) (Koiwai et al 1996).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

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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“…These findings suggest that genetic factors are involved in the development of neonatal hyperbilirubinemia. Recently, homozygous A(TA) 7 TAA variation in promoter of UGT1A1 gene was found to be associated with neonatal hyperbilirubinemia in Sephardic Jews (10), Americans (11), Italians (12,13), and British (14). However, in Japanese studies, the high allele-frequency of Gly71Arg in UGT1A1 gene was found to be responsible for neonatal hyperbilirubinemia without obvious cause (15,16).…”

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confidence: 99%

“…Very recently, we used the technique of PCR to determine the UGT1A1 gene in Taiwan Chinese adults and found that the occurrence of A(TA) 7 TAA allele was relatively rare (14.3% versus 40%) and the variation rate within the coding region was much higher (29.3% versus 0.1%) in Taiwan Chinese compared with Caucasians (17). In addition, we found a novel compound heterozygous variation within the coding region of the UGT1A1 gene that caused CN 2 in an adult patient (18).…”

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confidence: 99%

Relationship Between Bilirubin UDP-Glucuronosyl Transferase 1A1 Gene and Neonatal Hyperbilirubinemia

Huang

2002

Pediatric Research

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The variation rate within the coding region of UDPglucuronosyl transferase 1A1 (UGT1A1) gene in Taiwan Chinese was found to be 29.3%. This study sought to determine whether that high variation rate of UGT1A1 gene is a risk factor for neonatal hyperbilirubinemia. The study subjects consisted of 123 newborn infants suffering from unconjugated hyperbilirubinemia who had no known risk factors for hyperbilirubinemia and 218 healthy control neonates. The promoter area, exons 1 to 4, coding region of exon 5, and the flanking intronic regions in UGT1A1 gene were determined by the PCR in all subjects. Wild UGT1A1 gene, variation in the promoter, variation at nucleotide 211, variation at nucleotide 1091, and compound heterozygous variation of UGT1A1 gene were found. The percentage of neonates with wild UGT1A1 gene and the percentage of neonates with variation at nucleotide 211 were significantly different between the study subjects and controls. The percentages with bilirubin м342 M (20.0 mg/dL) and with persistent hyperbilirubinemia in the subjects carrying homozygous variation at nucleotide 211 (Gly71Arg) were significantly higher than the neonates carrying wild type or other genotypes. In conclusion, this study has demonstrated that variation at nucleotide 211 of the UGT1A1 gene is a risk factor for the development of neonatal hyperbilirubinemia. Pediatricians should closely follow hyperbilirubinemic newborn infants who carry homozygous 211 G to A variation in UGT1A1 gene. UDP-glucuronosyl transferase 1A1 (UGT1A1) is the key enzyme for bilirubin conjugation. Defects in this enzyme can cause a nonhemolytic unconjugated hyperbilirubinemia such as Crigler-Najjar syndrome type 1 (CN 1), type 2 (CN 2) and Gilbert's syndrome. Because UGT1A1 is too labile to be measured by classic biochemical methods, nonhemolytic unconjugated hyperbilirubinemia is ideally studied at the genetic level (1). The cDNA of human UGT1A1 gene was found to be located at chromosome 2q37 and was cloned in 1991 (1). This led to the detection of genetic defects in patients with CN 1 (2), CN 2 (3), and Gilbert's syndrome (4). CN 1 and Gilbert's syndrome have been shown to be mainly associated with mutations in exons 2 to 5 and promoter area, respectively (5).CN 2 and Gilbert's syndrome may be inherited as a recessive trait or as a dominant trait (4, 6, 7).The peak serum levels of unconjugated bilirubin in full-term Asian (Japanese, Korean, or Chinese) and American Indian neonates are double those in Caucasian and black populations (8). The incidence of kernicterus is also higher among Asian newborn infants (9). These findings suggest that genetic factors are involved in the development of neonatal hyperbilirubinemia. Recently, homozygous A(TA) 7 TAA variation in promoter of UGT1A1 gene was found to be associated with neonatal hyperbilirubinemia in Sephardic Jews (10), Americans (11), Italians (12,13), and British (14). However, in Japanese studies, the high allele-frequency of Gly71Arg in UGT1A1 gene was found to be responsible for neonatal hyperbilirubin...

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“…10,18) It has been suggested that Gilbert's syndrome comes from a dominant negative phenomenon by oligomerization composed of inactive monomer mutants. 19) In guinea pigs, the dimer of UGT is more active for morphine metabolism. 17) Opioid drugs are metabolized by UGT in liver, and morphine is metabolized by hUGT2B7 to the major product, morphine-3-glucoronide (M3G), and the minor product, morphine-6-glucuronide (M6G).…”

Section: Introductionmentioning

confidence: 99%

Substrate Specificity of Opioid Compounds to UDP-Glucuronosyltransferase (UGT), hUGT2B7 and Bovine Microsomal UGT

Iwamura

Ito

Kuno

et al. 2005

JOURNAL OF HEALTH SCIENCE

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We studied the substrate specificity of some opioid derivatives of 5,9-dimethyl-2′-hydroxybenzomorphan [1], composed of A, B, and D ring-systems of morphine, for human UDP-glucuronosyltransferase 2B7 (hUGT2B7), a typical glucuronidation enzyme to morphine and for bovine microsomal UGT. The group of nitrogen atom on the D ring (pyperidine ring) in [1] was modified with alkyl, alkenyl, alkynyl and aralkyl hydrocarbon substituents. hUGT2B7 did not react with the compounds with methyl and isopropyl groups on the nitrogen atom, but reacted with those having longer alkyl substituents of more than 3 carbon chains. Substances with alkenyl and isobutyl substituents are the best substrates (the Km value, 15 and 25 µM, respectively). Opioids with alkynyl and aralkyl hydrocarbon substituents are of low affinity (the Km value, 119 and 542 µM, respectively). Meanwhile, bovine enzyme did not react with opioid substances having methyl and isopropyl groups, like hUGT2B7. Bovine enzyme reacted well with opioid substances with alkenyl and alkynyl substituents on the same level as alkyl substituents. Thus, a clear difference between human UGT2B7 and bovine microsomal UGT was found in the reactivity of alkynyl group and this comes from species specificity. For development of effective opioid drugs, these results suggest that opioid compounds with short carbon substituents are better to maintain the effective level in the blood for a longer time, with low glucuronidation activity, as well as maintaining the analgesic potency of each drug.

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Crigler-Najjar syndrome type II is inherited both as a dominant and as a recessive trait

Cited by 63 publications

References 0 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

Relationship Between Bilirubin UDP-Glucuronosyl Transferase 1A1 Gene and Neonatal Hyperbilirubinemia

Substrate Specificity of Opioid Compounds to UDP-Glucuronosyltransferase (UGT), hUGT2B7 and Bovine Microsomal UGT

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