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Journal Article| Volume 266, ISSUE 35, P24048-24052, December 15, 1991

Molecular basis of multiple UDP-glucuronosyltransferase isoenzyme deficiencies in the hyperbilirubinemic rat (Gunn rat).

Open AccessPublished:December 15, 1991DOI:https://doi.org/10.1016/S0021-9258(18)54390-8
Molecular basis of multiple UDP-glucuronosyltransferase isoenzyme deficiencies in the hyperbilirubinemic rat (Gunn rat).
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      The Gunn rat is a mutant strain of Wistar rat which has unconjugated hyperbilirubinemia as a result of the absence of hepatic UDP-glucuronosyltransferase (UDPGT) activity toward bilirubin. The Gunn rat is also deficient in UDPGT activities toward phenol substrates, and also toward digitoxigenin-monodigitoxiside. We have demonstrated that the defect of the isoenzyme for 4-nitrophenol (4NP) in Gunn rat liver arises from a -1 frameshift mutation that removes 115 amino acids from the COOH terminus (Iyanagi, T., Watanabe, T., and Uchiyama, Y. (1989) J. Biol. Chem. 264, 21302-21307). To investigate the molecular basis of defects in other UDPGT isoenzymes, we isolated and sequenced cDNAs from a Gunn rat liver library using mutant 4NP-UDPGT cDNA as a probe. Three novel cDNAs were identified that had identical 3'-regions of 1362 base pairs containing a single-base deletion in the same position as that of the mutant 4NP-UDPGT cDNA. However, their 5'-regions, encoding the substrate-binding domain, showed no more than 40% homology to that of 4NP-UDPGT. These data provide evidence that defects in some UDPGT isoenzymes in the Gunn rat are caused by a single mutation that results in the formation of a common truncated COOH terminus. Furthermore, the data also suggest that these mRNAs are transcribed from a single gene and that the 5'-exons are transcribed independently and differentially spliced to common 3'-exons encoding the conserved domain.

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      Published online: December 15, 1991

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      DOI: https://doi.org/10.1016/S0021-9258(18)54390-8

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