Genetic lesions in bilirubin-UGT deficiency syndromes

Organization of the UGT1A gene. The organization of the UGT1A locus is depicted in the top panel. Four common exons (exons 2, 3, 4, and 5) are used in several UGT isoforms expressed from this locus. Upstream from these exons are a series of "unique" exons, only 1 of which is used in a given isoform. Each unique exon is preceded by a separate promoter (solid arrows). Splicing of exon 1A1 to the common region exons (2 to 5) generates the mRNA for bilirubin UGT (also termed UGT1A1). Genetic lesions in any of the 5 exons constituting the bilirubin UGT mRNA can abolish (Crigler-Najjar type I) or reduce (Crigler-Najjar type II) bilirubin-UGT activity. With type I, the genetic lesions may result in a premature stop codon or a single amino acid substitution. The sequence abnormalities can be located in the region encoding the signal peptide or other domains of the enzyme, or even in the introns at the splice donor or splice acceptor sites. Type II is caused by point mutations that result in substitution of a single amino acid. In contrast with Crigler-Najjar syndrome types I or II, Gilbert syndrome is caused by a promoter abnormality. Normally, the TATAA element within the promoter upstream to exon 1A1 consists of A(TA)6TAA. In Gilbert syndrome, 2 additional nucleotide residues (TA) are present in this element. Alleles containing the Gilbert-type promoter are termed UGT1A1*28. In addition, Japanese investigators have reported sequence abnormalities in the coding region of the gene that cause mild elevations of serum bilirubin concentrations, consistent with Gilbert syndrome.