Correlation of mutational analysis to clinical features in Taiwanese patients with Gilbert's syndrome

OBJECTIVES: Mutations in the promoter as well as in the coding region of th e 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 cla rified. METHODS: We applied polymerase chain reaction-based direct-sequencing assay s to examine mutations in UGT1A1 gene in 20 unrelated Gilbert's patients an d in a family with Gilbert's syndrome. RESULTS: We studied three mutations that were previously reported to be ass ociated with Gilbert's syndrome (i.e., the TATAA-box mutation, Gly71Arg, an d Pro229Gln) in 20 patients with Gilbert's syndrome. Of the patients, 16, f ive, and six were found to have the TATAA-box, Gly71Arg and Pro229Gln mutat ions, respectively. Seven patients had simultaneous mutations both in the T ATAA 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 c ontaining 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 hi gher than those found in the patients heterozygous for the TATAA-box mutati on alone. On the other hand, concurrence of Pro229Gln in patients with TATA A-box mutation or with Gly71Arg did not significantly affect serum bilirubi n levels. CONCLUSIONS: The TATAA-box mutation and Gly71Arg are the major causes for G ilbert's syndrome in our population. Concurrence of mutations of Gly71Arg a nd TATAA-box usually exerts a synergistic effect on hyperbilirubinemia. Pro 229Gln, which is regularly linked To the TATAA-box mutation, may not have a significant effect on serum bilirubin levels. (Am J Gastroenterol 2001;96: 1188-1193. (C) 2001 by Am. Coll. of Gastroenterology).