Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human UDP-glucuronosyltransferase (UGT) 1A1 is only enzyme in the conjugation of bilirubin for prevention of hyperbilirubinemia and jaundice. Deletion or mutation of the UGT1A1 gene causes Crigler-Najjar syndrome or Gilbert's syndrome. We previously reported the functional promoter region for expression of UGT1A1 [Hepatology Research 9, 152-163 (1997)]. We investigated the influence of some drugs on the transient transfection assay of the luciferase reporter gene containing the 5'-promoter region -3174/+14 of UGT1A1 in HepG2 cells. Among drugs investigated, dexamethasone was the most effective at the range of concentration of 10-100 microM, whereas stimulation by beta-estradiol was not found. We also could not find stimulation by bilirubin of the endogenous main substrate for UGT1A1. Stimulation by dexamethasone was continued for 48 hr. The luciferase reporter gene containing the 5'-region of -97/+14 was induced by dexamethasone but the gene of the 5'-region -53/+14 was not. The region -97/-53 is essential for induction by dexamethasone. This region contains HNF1 element, therefore, we speculated that dexamethasone directly and/or indirectly stimulates UGT1A1 expression through this HNF1 region in the promoter region of UGT1A1. Thus, we clarified that UGT1A1 was induced by dexamethasone and the key position was the region (-97/-53) in UGT1A1 promoter.
Mol Biol Rep 2004 Sep
PMID:Stimulation of transcriptional expression of human UDP-glucuronosyltransferase 1A1 by dexamethasone. 1556 Mar 69

We evaluated nonviral gene delivery into skeletal muscle via femoral artery and great saphenous vein for correction of hyperbilirubinemia in the Gunn rat, the animal model of Crigler-Najjar syndrome type I. A single injection of pDNA expressing hUGT1A1 under the CMV promoter resulted in excretion of bilirubin glucuronides in bile and a significant decrease in serum bilirubin for at least 2 or 4 weeks, respectively. Loss of metabolic effect was associated with a decrease in recombinant protein in muscle, while pDNA and transcript were detectable 4 weeks after gene delivery. Monthly intravenous gene delivery maintained metabolic correction for at least 5 months. Fibrosis around vessels in the arterial group limited the number of successful repeat gene transfer sessions to 3. Animals expressing hUGT1A1 developed anti-hUGT1A1 antibodies and lymphocytic infiltrate in muscle. Immunosuppression abrogated antibody response, ameliorated lymphocytic inflammation, and enhanced metabolic correction but did not prevent a decrease in the amount of recombinant protein. In conclusion, repeated intravenous delivery of pDNA into muscle enables long-term correction of hyperbilirubinemia in the Gunn rat. The procedure is safe and simple, with great clinical potential. Further studies are needed to explain the mechanisms of loss and improve the stability of recombinant hUGT1A1 in muscle.
Mol Ther 2005 Nov
PMID:Long-term correction of hyperbilirubinemia in the Gunn rat by repeated intravenous delivery of naked plasmid DNA into muscle. 1601 65

Crigler-Najjar type 1 disease (CN-1) is a genetic disorder characterized by high levels of unconjugated bilirubin due to the absence of hepatic UDPglucuronosyltransferase (UGT1) activity. Here we show that in vivo neonatal hepatocyte transduction with a lentiviral vector expressing the defective enzyme resulted in long-term correction in Gunn rats, a model of CN-1. Lentiviral vectors harboring the human UGT1 cDNA (approved symbol UGT1A1) under the control of a liver-specific transthyretin promoter were produced. Two-day-old Gunn rats were injected with 50 microl of vector. Bilirubinemia was monitored at 6 weeks and monthly thereafter. At 6 weeks, bilirubinemia was completely normalized in treated animals, whereas it remained around 100 microM in control rats. The level of correction remained stable for up to 42 weeks. Large amounts of bilirubin conjugates were present in the bile of corrected animals. PCR and Western blots confirmed the presence and expression of UGT1 in liver. The estimated proportion of transduced hepatocytes was 40% and transduced cells were not detected in extrahepatic tissues except bone marrow in some animals. This work represents the first demonstration of a complete and permanent correction of hyperbilirubinemia in Gunn rats using lentiviral vectors.
Mol Ther 2005 Nov
PMID:Therapeutic lentivirus-mediated neonatal in vivo gene therapy in hyperbilirubinemic Gunn rats. 1614 May 82

Oxidative stress plays an important role in the atherogenesis and bilirubin is one of the most potent antioxidant substances in human body. The aim of the present study was to investigate the impact of hyperbilirubinemia on plasma levels of advanced glycation end-products (AGEs), which contribute to atherogenesis. Two AGEs, pentosidine and Nepsilon-carboxymethyl lysine (CML), were determined in 23 subjects with Gilbert syndrome (GS) and in 21 age-matched healthy controls. Pentosidine was assessed by HPLC and CML was determined with ELISA. Logistic regression analysis was used for multiple adjustments of possible modifying factors. As expected, significantly higher serum bilirubin levels were found in GS subjects as compared to controls (28.9 +/- 9.6 vs 9.7 +/- 2.7 micromol/l, p<0.001). In contrast, serum levels of both AGEs were significantly lower in GS compared to normobilirubinemic controls (median; 25%-75% interquartile range (pentosidine: 1.12; 0.90-1.28 vs 1.31; 1.18-1.58 nmol/g protein, p<0.005; and CML: 6.70; 6.10-7.34 vs 7.33; 6.76-8.20 micromol/g protein, p = 0.01, respectively). Levels of both AGEs remained substantially lower even after adjustment for selected vascular risk and other modifying factors. In subjects with GS elevated serum bilirubin concentrations are associated with lower levels of AGEs. These results are in support of previous data on antioxidant properties of bilirubin.
Cell Mol Biol (Noisy-le-grand) 2005 Sep 30
PMID:Decreased levels of advanced glycation end-products in patients with Gilbert syndrome. 1630 89

Gilbert's syndrome is a mild hereditary unconjugated hyperbilirubinemia caused by mutations in the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). The causative mutation in Caucasians is almost exclusively a TA dinucleotide insertion in the TATA box of the UGT1A1 promoter. Affected individuals are homozygous for the variant promoter and have 7 instead of 6 TA repeats. The aim of the present study was to determine the genotypes of UGT1A1(TA)n promoter polymorphism in the healthy Slovenian population and to investigate the association of genotypes with serum bilirubin levels. 236 healthy subjects were genotyped by single-strand conformation polymorphism analysis, which was validated by sequence analysis. The frequencies of genotypes were as follows: (TA)(6/6) (38.1%), (TA)(6/7) (47.9%), (TA)(7/7) (13.6%). There was a statistically significant association of genotypes with serum bilirubin levels (p<0.001). Subjects with genotype (TA)(7/7) had the highest and subjects with genotype (TA)(6/6) the lowest total serum bilirubin levels. One individual in the group had the rare genotype (TA)(7/8) (0.4%). Analysis of his family showed the following genotypes: (TA)(6/8) in his father and sister and (TA)(7/8) in his two brothers. In conclusion, the frequency of UGT1A1(TA)n promoter polymorphism genotypes was determined for the first time in the Slovenian population and is similar to frequencies observed in other Caucasian populations. The extremely rare (TA)8 allele in Caucasians was found also in Slovenians.
Blood Cells Mol Dis
PMID:UGT1A1(TA)n promoter polymorphism--a new case of a (TA)8 allele in Caucasians. 1719 9

Citrin deficiency resulting from mutations of the SLC25A13 gene is associated with two major clinical phenotypes; neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type 2 citrullinemia (CTLN2). In Korea, 6 cases of citrin deficiency were diagnosed based on biochemical and molecular findings. Four NICCD patients (2 boys and 2 girls) presented high citrulline levels on a newborn screening test or neonatal cholestasis. They were associated with conjugated hyperbilirubinemia, elevated liver enzymes, hypoalbuminemia, mild hyperammonemia, elevated citrulline, methionine and threonine. All of the hepatic manifestations were resolved spontaneously at the age of 5-9 months. Mutation analysis identified them as compound heterozygotes carrying each of the c.851del4, IVS11+1G>A, IVS13+1G>A, G393S, and IVS16ins3kb mutant alleles. Two adult male CTLN2 patients were identified. They were aged 24 and 37 years, and presented sudden loss of consciousness, hyperammonemia and citrullinemia. They were compound heterozygotes with IVS13+1G>A and IVS16ins3kb, and with c.851del4 and IVS11+1G>A mutant alleles. This report describes the clinical characteristics, biochemical findings and molecular analysis of the SLC25A13 gene of patients with citrin deficiency in Korea.
Int J Mol Med 2007 Dec
PMID:Six cases of citrin deficiency in Korea. 1798 87

Hereditary pyrimidine 5'-nucleotidase deficiency is the most frequent enzymopathy of red blood cell nucleotide metabolism that causes hereditary non-spherocytic hemolytic anemia. The disease is usually characterized by mild-to-moderate hemolytic anemia, reticulocytosis and hyperbilirubinemia. To date, diagnosis ultimately depends upon demonstration of a reduced level of pyrimidine 5'-nucleotidase type-I (P5'N-1) activity in red cells and detection of mutations in the P5'N-1 gene. To unravel the causes of the P5'N deficiency and to obtain data for a definitive diagnosis three newly described missense mutations (c.187T>C, c.469G>C and c.740T>C) identified in patients with hemolytic anemia have been characterized at protein level. The mutant enzymes (C63R, G157R and I247T) were obtained as recombinant forms and purified to homogeneity. The enzymes were altered, although to a different extent, in both thermal stability and catalytic efficiency. The catalytic efficiency of all mutants was reduced especially towards UMP (up to more than 200 times), owing to the increased Km values (approximately, 10-25 times higher). The G157R enzyme was severely heat unstable and lost half of its activity after about 23 min of incubation at 37 degrees C. At higher temperature C63R and I247T mutants as well were less stable than the wild-type enzyme. Therefore, although the mutations targeted different regions of the P5'N-1 structure, they produced similar effects on the molecular properties of the enzyme. Thus, all affected amino acids are functionally and structurally important for preserving the enzyme activity during the red cell life span.
Blood Cells Mol Dis
PMID:Molecular basis of pyrimidine 5'-nucleotidase deficiency caused by 3 newly identified missense mutations (c.187T>C, c.469G>C and c.740T>C) and a tabulation of known mutations. 1849 1

Gilbert's syndrome causes mild, unconjugated hyperbilirubinemia and is present in approximately 10% of the Caucasian population. The basis of the disorder is a 70% reduction in bilirubin glucuronidation catalyzed by the UDP-glucuronosyltransferase 1A1 (UGT1A1), which, in Caucasians, is the result of a homozygous TA insertion into the promoter region of the UGT1A1 gene (UGT1A1*28). Homozygous carriers of UGT1A1*28 as well as those with additional UGT1A variants can suffer from severe irinotecan toxicity or jaundice during treatment with the protease inhibitor atazanavir. UGT1A1*28 genotyping identifies patients at risk for drug toxicity and can increase drug safety by dose individualization. Rapid and facile UGT1A1*28 genotyping is therefore of great clinical importance. Two hundred ninety-one patients with suspected Gilbert's syndrome were genotyped using the TaqMan 5'nuclease assay with minor groove binder-non fluorescent quench probes; results were confirmed by direct sequencing. Ninety-six patients (33%) were homozygous for UGT1A1*28, which was verified by direct sequencing of a different PCR product showing 100% concordance with the TaqMan PCR results. We describe a novel UGT1A1*28 genotyping method that employs allelic discrimination by TaqMan PCR. This assay provides a rapid, high-throughput, and cost-effective method for Gilbert's syndrome genotyping, which is of value for pretreatment screening of potential irinotecan toxicity. The method utilizes a technological platform that is widely used in clinical practice and could therefore be easily adapted for routine clinical applications.
J Mol Diagn 2008 Nov
PMID:Rapid allelic discrimination by TaqMan PCR for the detection of the Gilbert's syndrome marker UGT1A1*28. 1883 63

Glucose-6-phosphate deficiency is the most prevalent enzyme deficiency, with an estimated 400 million people affected worldwide. This inherited deficiency causes neonatal hyperbilirubinemia and chronic hemolytic anemia. Although most affected individuals are asymptomatic, exposure to oxidative stressors such as certain drugs or infection, can elicit acute hemolysis. To characterize the global prevalence of G6PD deficiency, we conducted a systematic review of the G6PD deficiency literature, drawing studies from various databases, including MEDLINE/Pubmed and Biosis. Selected studies included cross-sectional and longitudinal studies published between 1960 and 2008. Additionally, meta-analytic procedures were employed to assess the degree of heterogeneity amongst prevalence estimates and, where appropriate, pool them. The searches yielded a total of 280 prevalence estimates, corresponding to 88 countries. The highest prevalence rates were reported among Sub-Saharan African countries, even after adjusting for assessment method. Meta-analysis revealed a high degree of heterogeneity for regional and global prevalence estimates. This heterogeneity in reported estimates appeared to be due to differences in G6PD deficiency assessment and diagnostic procedures. The magnitude and variation in global, regional, and country-level prevalence rates of G6PD deficiency are of public health import, particularly in planning programs to improve neonatal health and in the distribution of various medications, especially antimalarial drugs, as G6PD deficiency is most prevalent in malaria-endemic areas.
Blood Cells Mol Dis
PMID:The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. 1923 95

Promoter variants c.-3279T>G and A(TA)7TAA show decreased level of expression of UDP-glucuronosyl transferase 1A1 (UGT1A1) and consequently reduced activity of the enzyme catalyzing glucuronidation of bilirubin in hepatocytes. Thus, coincidental occurence of both variants should lead to increase of hyperbilirubinemia or contribute to its manifestation. In this study, investigation of both variants in 101 patients and 84 controls in a Caucasian population was performed and the results were compared with serum bilirubin levels. Despite high linkage disequilibrium between the loci (D' = 0.91, r(2) = 0.69), we have proven an interaction between the variants increasing the odds ratio for [(TA)7]+c.[-3279T>G] homozygotes to 54.2.
Cell Mol Biol (Noisy-le-grand) 2009 Feb 16
PMID:Does bilirubin level correspond to interaction of c.-3279T>G and A(TA)7TAA variants in UGT1A1 gene? 1926 7


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