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UGT1A1 (TA)6/7 (UDP-glucuronosyl transferase 1A1, Gilbert's syndrome)UGT1A1 metabolizes primarily bilirubin but also drugs, xenobiotics and other endogenous compounds like hydroxyestrogens and thyroid hormones. Gilbert's syndrome, i.e. mild hyperbilirubinemia in adults enhanced by fasting, is mostly caused by common insertion / deletion mutations in the promoter of the UGT1A1 gene with 5, 6, 7 or 8 thymidine-adenine (TA) repeats. In caucasians, the wild type form is (TA)6 / (TA)6, and the most common mutation, (TA)7, occurs in 5-15 % of individuals (1). Molecular testing allows direct detection of theses abnormalities, so that the long series of serological and biochemical tests previously used to arrive at the exclusion diagnosis "Gilbert's syndrome" is no more necessary (2). In newborns with hemolytic syndromes (e.g. Rhesus or ABO bloodgroup incompatibility), pronounced icterus with the danger of kernicterus is associated with these UGT1A1 mutations (3). Notably, there are more than 50 other rare mutations in UGT1A1 that lead to either Gilbert's syndrome, or the more severe Crigler-Najaar syndrome of impaired bilirubin metabolism. Patients with variant UGT1A1 promoter genotypes are prone to toxicity of the cancer drug Irinotecan due to impaired glucuronidation of the active metabolite SN-38 (4). The antiretroviral drug Indinavir may precipitate jaundice in these patients due to competitive inhibition (5). Most patients with Gilbert's syndrome (see UGT1A1 (TA)6/7) also show the UGT1A6 T181A mutation, and may thus have abnormalities in glucuronidation of aspirin or coumarin- and dopamine-derivatives (6).References (1) Lampe JW, Bigler J, Horner NK, Potter JD. UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. Pharmacogenetics 1999 Jun;9(3):341-9 (PMID: 10471066)<Abstract> (2) Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat 2000 Oct;16(4):297-306 (PMID: 11013440)<Abstract> (3) Kaplan M, Hammerman C, Renbaum P, Klein G, Levy-Lahad E. Gilbert's syndrome and hyperbilirubinaemia in ABO-incompatible neonates. Lancet 2000 Aug 19;356(9230):652-3 (PMID: 10968441)<Abstract> (4) Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H, Yokoyama A, Saitoh S, Shimokata K, Hasegawa Y. Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 2000 Dec 15;60(24):6921-6 (PMID: 11156391)<Abstract> (5) Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, Feinberg J, Sherman KE. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci U S A 2001 Oct 23;98(22):12671-6 (PMID: 11606755)<Abstract> (6) Peters WH, te Morsche RH, Roelofs HM. Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert's syndrome. J Hepatol 2003 Jan;38(1):3-8 (PMID: 12480553)<Abstract> |