Molecular genetic basis of Gilbert's syndrome

Gilbert's syndrome, an hereditary, chronic, mild, unconjugated hyperbilirub inaemia resulting from impaired hepatic bilirubin clearance and otherwise n ormal liver function, is arguably the most common syndrome known in humans. Recent molecular genetic studies have determined that the clinical phenoty pe can be described by a dinucleotide polymorphism in the TATA box promoter of the bilirubin uridine diphosphate-glucuronosyltransferase (UGT-1A1) gen e, most frequently (TA)(7)TAA, affecting up to 36% of Africans, but only 3% of Asians. However, a second common heterozygous mutation in the coding ex on 1 of the UGT-1A1 gene (G71R) can also cause the Gilbert's phenotype in J apanese and Asians. The clinical phenotype may not be apparent as frequentl y as the determined genotype, due to environmental factors such as alcohol- induced hepatic bilirubin glucuronidation, reducing serum bilirubin levels and causing a latent condition. Gilbert's disease is a contributory factor of prolonged neonatal jaundice in breast-fed infants and may precipitate ja undice when coinherited with ether disorders of haem metabolism. The geneti c variation described as Gilbert's syndrome may lead to pharmacological var iation in drug glucuronidation and unexpected toxicity from therapeutic age nts. (C) 1999 Blackwell Science Asia Pty Ltd.