Takashi Iyanagi: UGT1 gene complex: from Gunn rat to human

Abstract

UDP-glucuronosyltransferases (UGT) comprise a large gene superfamily that can be classified, based on the degree of amino-acid similarity between isoforms, into several gene families. Among these gene families, the UDP-glucuronosyltransferase family 1 (UGT1) gene is a unique gene complex organized to generate enzymes that share a common carboxyl terminal portion and are unique in the variable amino terminal region. Each variable exon I is preceded by a regulatory 5’-region and, in response to a specific signal, transcription processing splices mRNA from each unique exon 1 to the four common exons ( 2, 3, 4, and 5) to provide a template for synthesis of the individual isoforms. A novel clue to elucidate the gene structure of mammalian UGT1 was cDNA cloning of rat UGT1A6 from the hyperbilirubinemic Gunn rat by Professor Takashi Iyanagi Ph.D. The elucidation of the structure of the rat UGT1 gene complex has led to a greater understanding of the genetic basis of Crigler-Najjar and Gilbert’s syndromes. Now, examination of the UGT1 gene structure in hyperbilirubinemic patients has revealed more than 100 different genetic defects in Crigler-Najjar syndromes and one genetic alternation that accounts for the majority of Gilbert’s syndrome cases. This review of a chapter in UGT history will focus on the extensive research of Iyanagi and coworkers with the rat UGT1 gene complex and advancing to the study of the human gene.

Keywords::

• Bilirubin
• Crigler-Najjar syndrome
• Gilbert’s syndrome
• hyperbilirubinemia
• isoform
• UDP-glucuronosyltransferase

Acknowledgements

This work was supported, in part, by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and culture of Japan (20580138).