Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus

The original novel UCT1 complex locus previously shown to encode six differ ent UDP-glucuronosyltransferase (transferase) genes has been extended and d emonstrated to specify a total of IS isoforms, The genes are designated UGT 1A1 through UGT1A13p with four pseudo ones. UGT1A2p and UGT1A11p through UG T1A13p have either nucleotide deletions or flawed TATA boxes and are theref ore pseudo. In the 5' region of the locus, the 13 unique exons 1 are arrang ed in a tandem array with each having its own proximal TATA box element and , in turn, are linked to four common exons to allow for the independent tra nscriptional initiation to generate overlapping primary transcripts. Only t he lead exon in the nine viable primary transcripts is predicted to undergo splicing to the four common exons generating mRNAs with identical 3' ends and transferase isozymes with an identical carboxyl terminus. The unique am ino terminus specifies acceptor-substrate selection, and the common carboxy l terminus apparently specifies the interaction with the common donor subst rate, UDP-glucuronic acid. in the extended region, the viable TATA boxes ar e either A(A)T(9)A(AA)T or AT(14)AT; in the original locus the element for UGT1A1 is A(TA)(7)A and TAATT/CAA(A) for all of the other genes. UGT1A1 spe cifies the critically important bilirubin transferase isoform, The relation ships of the exons 1 to each other are as follows: UGT1A2p through UGT1A5 c omprises a cluster A that is 87-92% identical, and UGT1A7 through UGT1A13p comprises a cluster B that is 67-91% identical. For the two not included in a cluster, UGT1A1 is more identical to cluster A at 60-63%, whereas UGT1A6 is identical by between 48% and 56% to all other unique exons, The locus w as expanded from 95 kb to 218 kb, Extensive probing of clones beyond 218 li b with coding nucleotides for a highly conserved amino acid sequence presen t in all transferases was unable to detect other exons 1. The mRNAs are dif ferentially expressed in hepatic and extrahepatic tissues. This locus is in deed novel, indicating the least usage of exon sequences in specifying diff erent transferase isozymes that have an expansive substrate range. Pharmaco genetics 11:357-368 (C) 2001 Lippincott Williams & Wilkins.