title: Hyperbilirubinaemia in heterozygous beta-thalassaemia is related to co-inherited Gilbert's syndrome.
abstract: The reasons why heterozygotes for beta-thalassaemia have considerable variation in serum bilirubin levels are unknown. High levels of bilirubin could be related to the co-inherited Gilbert's syndrome, determined either by mutations of the coding region or by variation in the A(TA)nTAA motif of the promoter of the bilirubin UDP-glucuronosyltransferase gene (UGT-1). We sequenced the coding and the promoter region of UGT-1A or characterized the A(TA)nTAA motif of the promoter by denaturing gel electrophoresis of radioactive amplified products. The results were correlated with bilirubin levels in 49 beta-thalassaemia heterozygotes for codon 39 (CAG --> TAG) nonsense mutation. 21 normal individuals and 32 unrelated patients with Gilbert's syndrome served as controls. The coding sequence region of the UGT-1A was normal. Five beta-thalassaemia heterozygotes, who were homozygous for the extra (TA) bases in the A(TA)nTAA element of the promoter of UGT-1A, the configuration present in homozygosity in Gilbert's syndrome, had higher bilirubin levels compared to those with the (TA)6/(TA)7 or (TA)6/(TA)6 configurations. In the group of 32 patients with Gilbert's syndrome, 31 of whom had the (TA)7/(TA)7 configuration, we detected 14 heterozygotes for beta-thalassaemia, a figure much higher than predicted on the basis of the carrier rate. Homozygosity for the (TA)7 motif, the typical promoter configuration of Gilbert's syndrome, is one of the factors determining hyperbilirubinaemia in heterozygous beta-thalassaemia.
authors.affiliation: Istituto di Clinica e Biologia dell'Età Evolutiva Ospedale Regionale Microcitemie, Cagliari, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Galanello
authors.forename: L
authors.initials: L
authors.lastname: Perseu
authors.forename: M A
authors.initials: MA
authors.lastname: Melis
authors.forename: L
authors.initials: L
authors.lastname: Cipollina
authors.forename: S
authors.initials: S
authors.lastname: Barella
authors.forename: N
authors.initials: N
authors.lastname: Giagu
authors.forename: M P
authors.initials: MP
authors.lastname: Turco
authors.forename: O
authors.initials: O
authors.lastname: Maccioni
authors.forename: A
authors.initials: A
authors.lastname: Cao
mesh_terms: D005838:Genotype; D005878:Gilbert Disease / Q000235:genetics*; D005914:Globins / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D006932:Hyperbilirubinemia / Q000235:genetics*; D009154:Mutation; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D005914:Globins