A NEW-TYPE OF DEFECT IN THE GENE FOR BILIRUBIN URIDINE 5'-DIPHOSPHATE-GLUCURONOSYLTRANSFERASE IN A PATIENT WITH CRIGIER-NAJJAR SYNDROME TYPE-I

Crigler-Najjar syndrome (CN) type I, which is characterized by the com plete absence of bilirubin uridine 5'-diphosphate-glucuronosyltransfer ase (UGT) activity, is inherited as an autosomal recessive trait assoc iated with unconjugated hyperbilirubinemia. Phenobarbital has no effec t on the bilirubin concentration in the serum of patients with CN type I. Recently, cDNA for two human liver bilirubin UGT (UGT1A and UGT1D) were isolated, and their genetic organization was determined. The UGT 1A (UGT11) and UGT1D (UGT1*4) genes each have a unique exon 1, wherea s exons 2-5 are common to both genes. It has been predicted that some defect in the exons common to both genes is responsible for the absenc e of UGT1A and UGT1D activities in CN type I, and five cases with such a mutation have been reported. We describe here a new type of defect in the gene for bilirubin UGT in a patient with CN type I, namely, an abnormality in the exon 1 that is characteristic of the UGT1A gene. Th is mutation is a single nucleotide substitution, that is, C is changed to A at base position 840 in UGT1A. cDNA, and this change results in a stop codon. Our patient is homozygous for the defect, and his noncon sanguineous parents and elder brother, who are clinically normal, are heterozygous for the defective allele. No mutation was detected in any exons of the UGT1D gene. Our results suggest that a homozygous nonsen se or deletion mutation is detected not only in the exons common to UG T1A and UGT1D genes but also in unique exon 1 of UGT1A in CN type I.