Molecular pathogenesis of Gilbert's syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter

Hsieh, Tsai‐Yuan; Shiu, Tzu-Yue; Huang, Shih‐Ming; Lin, Hsuan-Hwai; Lee, Tai-Chi; Chen, Peng‐Jen; Chu, Heng-Cheng; Chang, Wei‐Kuo; Jeng, King‐Song; Lai, Michael M. C.; Chao, You‐Chen

doi:10.1097/fpc.0b013e328012d0da

Cited by 65 publications

(39 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Though rarely identified in other populations, two additional repeat alleles, (TA) 5 and (TA) 8, are also present at low frequency in people of recent African descent (Beutler et al, 1998;Premawardhena et al, 2003). There is a negative association between UGT1A1 expression and repeat length of the four alleles, attributable to decreasing promoter activity acting via altered affinity for the TATA-binding protein (Beutler et al, 1998;Hsieh et al, 2007). Although the (TA) n alleles appear to have similar effects on bilirubin levels in people of recent African descent (Chaar et al, 2005;Hong et al, 2007;Carpenter et al, 2008) and low-activity alleles confer significantly raised risk of developing gallstones requiring surgery (Passon et al, 2001;Heeney et al, 2003), Gilbert's syndrome is rarely diagnosed in Africa (Bougouma et al, 1999).…”

Section: Introductionmentioning

confidence: 96%

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

Horsfall

Zeitlyn

Tarekegn

et al. 2011

Annals of Human Genetics

View full text Add to dashboard Cite

SummaryVariation of a short (TA) n repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDPglucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA) 7 and (TA) 8 )) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA) n alleles frequencies were highest in equatorial Africa, (TA) 7, being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA) n . Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA) n on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.

show abstract

Section: Introductionmentioning

confidence: 96%

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

Horsfall

Zeitlyn

Tarekegn

et al. 2011

Annals of Human Genetics

View full text Add to dashboard Cite

show abstract

“…Most patients presenting with this disease are homozygous [A(TA) 7 TAA/A(TA) 7 TAA] for a TA insertion in the TATA box of the UGT1A1 gene promoter and have a 70% reduction in the glucuronidation of bilirubin (7,8). Hyperbilirubinemia may increase under certain conditions, such as prolonged fasting, especially fats, fever or infections.…”

Section: Study Of a Family In The Province Of Matera Presentingmentioning

confidence: 99%

“…In different populations, there are a number of thymine-adenine (TA) repeats varying from 5 to 8, with an inverse correlation between promoter activity and number of TA repetitions: A(TA) 8 TAA promoter with reduced activity, A(TA) 7 TAA promoter with reduced activity (UGT1A1 * 28), A(TA) 6 TAA wild-type and A(TA) 5 TAA promoter with increased activity.…”

Section: Introductionmentioning

confidence: 99%

Study of a family in the province of Matera presenting with glucose-6-phosphate dehydrogenase deficiency and Gilbert's syndrome

et al. 2012

View full text Add to dashboard Cite

Abstract. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a recessive X-linked trait, is the most common enzyme deficiency in the world. The most devastating clinical consequence of this deficit is severe neonatal jaundice, which results in sensorineural deficit, and severe haemolytic anemia. However, patients may be asymptomatic. The most common clinical sign is hyperbilirubinemia (h↑), that is also related to Gilbert's syndrome, a condition associated with the promoter polymorphism of the UDP-glucuronosyltransferase 1 (UGT1A1) gene. The aim of this study was to underline (as is usually done by DNA molecular analysis) to detect and to clarify the genetic deficiency that is the reason of the disorder in question. In this study, different techniques were applied to analyse a family of four individuals presenting with hyperbilirubinemia: bilirubinic dosage, electrophoresis and enzymatic activity dosage of G6PD; molecular analysis of the UGT1A promoter to detect a thymine-adenine (TA) insertion, that causes the [A(TA) 7 TAA] mutation. The results showed that in certain cases, the presence of hyperbilirubinemia is not only associated with G6PD deficiency, but may be caused by the co-presence of a mutation in the UGTA1 promoter related to Gilbert's syndrome. As being affected by these two conditions predisposes to adverse effects towards certain drug treatments, it is advisable to study the UGTA1 gene before prescribing drugs for specific antineoplastic or retroviral tratment. We emphasize that investigating both the UGT1A gene and G6PD activity is the most reliable way to make a correct differential diagnosis.

show abstract

“…The genetic variants of the uridine 5'-diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene, specifically in the TATA-box of the promoter region, might reduce the transcription activity of the gene and UGT1A1 enzyme concentration, to ultimately affect conjugation (hepatic glucuronidation) capacity, which results in Gilbert's syndrome (Bosma et al, 1995;Monaghan et al, 1996;Raijmakers et al, 2000;Hsieh et al, 2007). Affected subjects may experience an impairment in drug elimination as well as severe adverse effects from drug metabolites (e.g., acetaminophen, irinotecan, SN-38, indinavir) (de Morais et al, 1992;Ando et al, 1998Ando et al, , 2000Burchell et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Rapid molecular diagnosis of the Gilbert's syndrome-associated exon 1 mutation within the UGT1A1 gene

Hsieh¹,

Shiu²,

Chu³

et al. 2014

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. Gilbert's syndrome is suspected in patients with unconjugated hyperbilirubinemia caused by decreased activity of the UDP-glucuronosyltransferase 1A1 (UGT1A1) gene in the absence of abnormal liver function and hemolysis. The major genetic variants underlying Gilbert's syndrome are TATA-box repeats of the promoter region and exon 1 G211A of the coding region, particularly in Asians. The efficacy of DNA melting curve analysis, however, has not been established for the G211A mutation. For rapid and accurate molecular diagnosis of Gilbert's syndrome, DNA melting curve analysis was evaluated for its genotyping capability not only for TATA-box Rapid diagnosis of exon 1 mutant within the UGT1A1 gene repeats of the UGT1A1 promoter, but also for G211A of UGT1A1 exon 1. TA repeats within the TATA-box sequence and the exon 1 G211A mutation of the UGT1A1 gene were analyzed by DNA melting curve analysis. To evaluate the assay reliability, direct sequencing or polyacrylamide gel electrophoresis was used as a comparative method. All homozygous and heterozygous polymorphisms of A(TA) 7 TAA within the TATA-box allele and of exon 1 G211A mutants of the UGT1A1 gene were successfully identified with DNA melting curve analysis. DNA melting curve analysis is, therefore, an effective molecular method for the rapid diagnosis of Gilbert's syndrome, as it detects not only TATA-box polymorphisms but also the exon 1 G211A mutation located within the UGT1A1 gene.

show abstract

Molecular pathogenesis of Gilbert's syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter

Abstract: TA insertion in the TATA-box-like sequence of the UGT1A1 promoter affected its binding affinity for TATA-binding protein, causing a decrease in its activity. This explains the pathogenesis of Gilbert's syndrome.

Cited by 65 publications

References 45 publications

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

Study of a family in the province of Matera presenting with glucose-6-phosphate dehydrogenase deficiency and Gilbert's syndrome

Rapid molecular diagnosis of the Gilbert's syndrome-associated exon 1 mutation within the UGT1A1 gene

Contact Info

Product

Resources

About