THE GENETIC-BASIS OF THE REDUCED EXPRESSION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE-1 IN GILBERTS-SYNDROME

Background. People with Gilbert's syndrome have mild, chronic unconjug ated hyperbilirubinemia in the absence of liver disease or overt hemol ysis. Hepatic glucuronidating activity, essential for efficient biliar y excretion of bilirubin, is reduced to about 30 percent of normal. Me thods. We sequenced the coding and promoter regions of the gene for bi lirubin UDP-glucuronosyltransferase 1 (bilirubin/uridine diphosphogluc uronate-glucuronosyltransferase 1) - the only enzyme that contributes substantially to bi[irubin glucuronidation - in 10 unrelated patients with Gilbert's syndrome, 16 members of a kindred with a history of Cri gler-Najjar syndrome type II, and 55 normal subjects. Results. The cod ing region of the gene for the enzyme was normal in the 10 patients wi th Gilbert's syndrome. These patients were homozygous for two extra ba ses (TA) in the TATAA element of the 5' promoter region of the gene (A (TA)(7)TAA rather than the normal A(TA)(6)TAA). The presence of the. l onger TATAA element resulted in the reduced expression of a reporter g ene, encoding firefly luciferase, in a human hepatoma cell line. The f requency of the abnormal allele was 40 percent among the normal subjec ts. The 3 men in the control group who were homozygous for the longer TATAA element had significantly higher serum bilirubin levels than the other 52 normal subjects (P = 0.009). Among the kindred with a histor y of Crigler-Najjar syndrome type II, only the six heterozygous carrie rs who had a longer TATAA element on the structurally normal allele ha d mild hyperbilirubinemia, characteristic of Gilbert's syndrome. Concl usions. Reduced expression of bilirubin UDP-glucuronosyltransferase 1 due to an abnormality in the promoter region of the gene for this enzy me appears to be necessary for Gilbert's syndrome but not sufficient f or the complete manifestation of the syndrome.