GENETIC-DEFECTS OF THE UDP-GLUCURONOSYLTRANSFERASE-1 (UGT1) GENE THATCAUSE FAMILIAL NONHEMOLYTIC UNCONJUGATED HYPERBILIRUBINEMIAS

Congenital familial non-haemolytic hyperbilirubinaemias are potentiall y lethal syndromes caused by genetic lesions that reduce or abolish he patic bilirubin UDP-glucuronosyltransferase activity. Here we describe genetic defects that occur in the UGT1 gene complex that cause three non-haemolytic unconjugated hyperbilirubinaemia syndromes. The most se vere syndrome, termed Crigler-Najjar syndrome type I, is mainly associ ated with mutations in exons 2 to 5 that affect all UGT1 enzymes and m any of the mutations result in termination codons and frameshifts. Cri gler-Najjar type II syndrome which is treatable with phenobarbital the rapy is associated with less dramatic missense mutations or heterozygo us expression of mutant and normal alleles. Gilbert's syndrome, the mo st prevalent (2-19% in population studies) and mildest of the three sy ndromes is principally caused by a TA insertion at the TATA promoter r egion upstream of the UGT1A1 exon. Current methods used for the diagno sis and treatment of these diseases are discussed. (C) 1997 Elsevier S cience B.V.