Molecular genetic basis of Gilbert's syndrome.
Gilbert's syndrome, an hereditary, chronic, mild, unconjugated hyperbilirubinaemia resulting from impaired hepatic bilirubin clearance and otherwise normal liver function, is arguably the most common syndrome known in humans. Recent molecular genetic studies have determined that the clinical phenotype can be described by a dinucleotide polymorphism in the TATA box promoter of the bilirubin uridine diphosphate-glucuronosyltransferase (UGT-1A1) gene, most frequently (TA)7TAA, affecting up to 36% of Africans, but only 3% of Asians. However, a second common heterozygous mutation in the coding exon 1 of the UGT-1A1 gene (G71R) can also cause the Gilbert's phenotype in Japanese and Asians. The clinical phenotype may not be apparent as frequently 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 jaundice when coinherited with other disorders of haem metabolism. The genetic variation described as Gilbert's syndrome may lead to pharmacological variation in drug glucuronidation and unexpected toxicity from therapeutic agents.
Burchell
B
B
Department of Molecular and Cellular Pathology, Ninewells Medical School, The University, Dundee, Scotland. b.burchell@dundee.ac.uk
Hume
R
R
D005838:Genotype; D005878:Gilbert Disease / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D006932:Hyperbilirubinemia / Q000175:diagnosis / Q000235:genetics; D008658:Inactivation, Metabolic; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000175:diagnosis / Q000235:genetics; D008297:Male; D010375:Pedigree; D010641:Phenotype; D016385:TATA Box / Q000235:genetics
D020719:Glucuronides; D014453:Glucuronosyltransferase