Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia.

The UDP-glucuronosyltransferase UGT1A1 plays a critical role in the detoxification of potentially neurotoxic bilirubin by conjugating it with glucuronic acid. We identified a polymorphism that results in a T to G substitution at nucleotide number -3263 of the phenobarbital-responsive enhancer module of the UGT1A1 gene, thereby significantly decreasing transcriptional activity as indicated by the luciferase-reporter assay. At least one T-3263G allele was found in 21 of 25 subjects with mild hyperbilirubinemia (Gilbert's syndrome); this frequency (0.58) was significantly higher than that in normobilirubinemic controls (0.17; n = 8 of 27). Homozygous mutations in the TATA element (A[TA](7)TAA) or at nucleotide 211 of exon 1 (G to A substitution) were found in 5 and 2 of the hyperbilirubinemic group, respectively, while 12 of these subjects were double heterozygotes for the T-3263G and G211A mutations. Plasma total bilirubin levels in these double heterozygotes were significantly higher than those in control subjects carrying one or other of these mutations singly, indicating that compound heterozygous mutations may result in more strongly reduced UGT1A1 activity. Our results indicate that homozygosity and compound heterozygosity for mutations in the UGT1A1 gene promoter (T-3263G and A[TA](7)TAA) and/or exon 1 of the gene (G211A) could explain the hyperbilirubinemia seen in the majority of individuals with Gilbert's syndrome.