Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: Correlation of genotype to phenotype

Uridine-diphosphoglucuronate glucuronosyltransferases (UGTs) are a family o f enzymes that conjugate various endogenous and exogenous compounds with gl ucuronic acid and facilitate their excretion in the bile. Bilirubin-UGT(1) (UGT1A1) is the only isoform that significantly contributes to the conjugat ion of bilirubin. Lesions in the gene encoding bilirubin-UGT(1), lead to co mplete or partial inactivation of the enzyme causing the rare autosomal rec essively inherited conditions, Crigler-Najjar syndrome type-1 (CN-1) and ty pe 2 (CN-2), respectively. Inactivation of the enzyme leads to accumulation of unconjugated bilirubin in the serum. Severe hyperbilirubinemia seen in CN-1 can cause bilirubin encephalopathy (kernicterus). Kernicterus can be f atal or may leave behind permanent neurological sequelae, Here, we have com piled more than 50 genetic lesions of UGT1A1 that cause CN-1 (including 9 n ovel mutations) or CN-2 (including 3 novel mutations) and have presented a correlation of structure to function of UGT1A1. In contrast to Crigler-Najj ar syndromes, Gilbert syndrome is a common inherited condition characterize d by mild hyperbilirubinemia. An insertional mutation of the TATAA element upstream to UGT1A1 results in a reduced Level of expression of the gene. Ho mozygosity for the variant promoter is required for Gilbert syndrome, but n ot sufficient for manifestation of hyperbilirubinemia, which is partly depe ndent on the rate of bilirubin production. Several structural mutations of UGT1A1, for example, a G71R substitution, have been reported to cause mild reduction of UGT activity toward bilirubin, resulting in mild hyperbilirubi nemia, consistent with Gilbert syndrome. When the normal allele of a hetero zygote carrier for a Crigler-Najjar type structural mutation contains a Gil bert type promoter intermediate levels of hyperbilirubinemia, consistent wi th the diagnosis of CN-2, may be observed. Hum Mutat 16:297-306, 2000, (C) 2000 Wiley-Liss, Inc.