Bilirubin‐UDP‐glucuronosyltransferase: Genetic defect of the hyperbilirubinemic gunn rat, a model of crigler‐najjar syndrome type I

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The hyperbilirubinemic Gunn rat lacks hepatic uridine diphosphate-glucuronosyltransferase (UDPGT) activity toward bilirubin, and has been used as an animal model for human Crigler-Najjar syndrome type I. Although the rat was discovered 50 years ago as a useful model of the disease, the gene encoding the enzyme had not yet been isolated. We isolated the bilirubin UDPGT cDNA from the cDNA library of a normal rat and revealed that the cDNA shared an identical 913 bp sequence (corresponding to the 247 carboxyl-terminal amino acid residues) with that for phenol UDPGT, whose activity was also deficient in the Gunn rat. The genetic defect of bilirubin UDPGT in the mutant rat was proved to be a -1 frameshift mutation. The mutation was found not only to be located in the region where the cDNA for bilirubin UDPGT shared the identical sequence with that for phenol UDPGT, but it also occurred in the same position in the two cDNA from the mutant. At the 5′ end of the identical region there was a consensus sequence for splicing. In addition, both the bilirubin and phenol UDPGT genes were mapped at position 37 on mouse chromosome 1 by an analysis of restriction endonuclease fragment length variations using the rat bilirubin and phenol UDPGT cDNA as probes. These results indicate that both UDPGTs are transcribed by alternative use of promotors and that a point frameshift mutation on a common exon produced the multiple defects of UDPGT isozymes observed in the homozygous Gunn rat. Accordingly, Gunn rats are an interesting model for the study of gene therapy of genetic liver diseases. Introduction of bilirubin UDPGT cDNA into the liver of Gunn rat by retrovirus-mediated gene transfer showed a significant and stable correction of the hyperbilirubinemia. Recent studies of the genomic structure of bilirubin UDPGT are also briefly described.