title: Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects.
abstract: Recent research has shown that congenital nonhemolytic low grade hyperbilirubinemias in patients with Gilbert's syndrome (GS) are linked to mutations in the TATA box upstream of the uridine 5'-diphosphoglucose glucuronosyltransferase (UGT1A1) gene leading to an impaired bilirubin glucuronidation. In routine clinical practice GS patients can, however, only be suspected by exclusion of other causes of hyperbilirubinemia or substantial liver diseases. We developed a new, sensitive, convenient, and economic polymerase chain reaction (PCR) method for the rapid and reliable identification of gene polymorphisms in the TATA box of the UGT1A1 gene using fluorescence resonance energy transfer (FRET). With this procedure the genotype frequency in a cohort of 266 unrelated individuals from Southern Germany was investigated and the allelic distribution for individual genotypes was 43:45:12 for the (TA)(6)TAA:(TA)(6)TAA/(TA)(7)TAA:(TA)(7)TAA alleles, respectively. The homozygous (TA)(7)TAA genotype was strongly associated with suspected Gilbert's patients and its prevalence in our cohort of 266 Southern German individuals was 12.4%. In this cohort total mean serum bilirubin levels ranged from 5 micromol/L (wild-type 6/6 allele) to 57 micromol/L serum total bilirubin (mutant 7/7 homozygous allele). Median (interquartile range) serum total bilirubin levels were 12 (6) and 21 (13) for the homozygous wild-type and mutant allele, respectively. Our assay enables individual guidance for dose adjustment in suspected GS patients undergoing long-term drug therapies, especially if glucuronidation via UGT1A1 is a major metabolic pathway.
authors.affiliation: Fraunhofer Institute of Toxicology and Aerosol Research, Department of Molecular Toxicology and Pharmacokinetics, Hannover, Germany. Borlak@ita.fhg.de
authors.forename: J
authors.initials: J
authors.lastname: Borlak
authors.forename: T
authors.initials: T
authors.lastname: Thum
authors.forename: O
authors.initials: O
authors.lastname: Landt
authors.forename: K
authors.initials: K
authors.lastname: Erb
authors.forename: R
authors.initials: R
authors.lastname: Hermann
mesh_terms: D000328:Adult; D001663:Bilirubin / Q000097:blood; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005838:Genotype; D005878:Gilbert Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D016385:TATA Box
chemical_list: D014453:Glucuronosyltransferase; D001663:Bilirubin