Objectives: Mutations in the promoter as well as in the coding region of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1) have been found to be associated with Gilbert's syndrome. However, the genetic basis of Gilbert's syndrome in our population and correlation of these mutations to fasting serum bilirubin levels in patients with Gilbert's syndrome remain to be clarified.
Methods: We applied polymerase chain reaction-based direct-sequencing assays to examine mutations in UGT1A1 gene in 20 unrelated Gilbert's patients and in a family with Gilbert's syndrome.
Results: We studied three mutations that were previously reported to be associated with Gilbert's syndrome (i.e., the TATAA-box mutation, Gly71Arg, and Pro229Gln) in 20 patients with Gilbert's syndrome. Of the patients, 16, five, and six were found to have the TATAA-box, Gly71Arg and Pro229Gln mutations, respectively. Seven patients had simultaneous mutations both in the TATAA box and in the coding region. Of note, all six patients with Pro229Gln also had the TATAA-box mutation. Localization of Pro229Gln on the allele containing the TATAA-box mutation was demonstrated in a family with Gilbert's syndrome. The patients simultaneously heterozygous for both the TATAA-box mutation and Gly71Arg usually had serum bilirubin levels similar to those found in the patients homozygous for the TATAA-box mutation, but usually higher than those found in the patients heterozygous for the TATAA-box mutation alone. On the other hand, concurrence of Pro229Gln in patients with TATAA-box mutation or with Gly71Arg did not significantly affect serum bilirubin levels.
Conclusions: The TATAA-box mutation and Gly71Arg are the major causes for Gilbert's syndrome in our population. Concurrence of mutations of Gly71Arg and TATAA-box usually exerts a synergistic effect on hyperbilirubinemia. Pro229Gln, which is regularly linked to the TATAA-box mutation, may not have a significant effect on serum bilirubin levels.