Crigler-Najjar syndrome type II resulting from three different mutations in the bilirubin uridine 5′-diphosphate-glucuronosyltransferase (UGT1A1) gene

Editor—Crigler-Najjar syndromes (CN, MIM 218800) are inborn errors of metabolism characterised by unconjugated hyperbilirubinaemia resulting from the defective activity of the hepatic enzyme bilirubin uridine 5′-diphosphate-glucuronosyltransferase (B-UGT). CN syndrome has been classified into two types according to the degree of hyperbilirubinaemia and to the response to phenobarbital administration. The more severe CN type I is characterised by severe chronic non-haemolytic unconjugated hyperbilirubinaemia with high levels of serum bilirubin owing to the absence of bilirubin UGT activity. In the milder CN type II, bilirubin UGT activity is only decreased and a consistently significant reduction is obtained with phenobarbital treatment, which does not occur in CN I. Like other members of the UGT isozyme family, the two human liver bilirubin UGT isozymes, UGT1A1 and UGT1D, are encoded by the UGT1 gene complex through a mechanism of alternative splicing. Each gene has a unique promoter and a unique exon 1, while exons 2-5 are common to both genes.1 Most of the enzymatic activity results from the expression of the UGT1A1 gene.2 At the molecular level, CN I results from a number of different defects; nonsense (or frameshift) and missense mutations are represented in almost the same amounts both in homozygosity and in the compound heterozygous state.3 4 The milder phenotype in CN II patients seems to be mainly the result of homozygosity for missense mutations5 and more …