The UGT1A1 gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first exons followed by four common exons. Four of the alternate first exons are considered pseudogenes. Each of the remaining nine 5' exons may be spliced to the four common exons, resulting in nine proteins with different N-termini and identical C-termini. Each first exon encodes the substrate binding site, and is regulated by its own promoter.
Mutations in this gene cause serious problems for bilirubin metabolism; each syndrome can be caused by one or many mutations, so they are differentiated mostly by symptoms and not particular mutations:
Gilbert syndrome (GS) in many populations, other than southeast and east Asians and Pacific Islanders, is most commonly associated with a homozygous 2-bpinsertion (TA) mutation of the TATA boxpromoter region of the UGT1A1 gene, a polymorphism found in 40% of the alleles of many populations. About 10-15% of these populations are homozygous, but fewer (about 5%) actually develop UGT1A1-associated hyperbilirubinemia, so it appears that this mutation alone may be a necessary but not sufficient factor in GS, perhaps acting in combination with other UGT1A1 mutation(s) to increase the chances of developing GS. In the populations mentioned, since the TATA box mutation is much less common (about 3% of alleles), Gilbert's syndrome is more often due to missense mutations of the actual encoding region of the gene. A special phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3) helps to increase UDPGT enzyme production, which would make it conceptually possible to medically control the bilirubin level, although this is rarely necessary, particularly in adults (usually the level of total serum bilirubin in Gilbert syndrome patients vary from 1 to 6 mg/dL).
Crigler-Najjar syndrome, type I is associated with mutation(s) that result in a complete absence of normal UDPGT enzyme, which causes a severe hyperbilirubinemia with levels of total serum bilirubin from 20 to 45 mg/dL. Phenobarbital treatment does not help to lower bilirubin level, because it only increases the amount of mutated UDPGT enzyme, which is still unable to catalyze the glucuronidation of bilirubin, which on the other hand makes phenobarbital treatment diagnostically relevant.
Crigler-Najjar syndrome, type II is associated with other mutation(s) that lead to a reduced activity of the mutated UDPGT enzyme, which causes a hyperbilirubinemia with levels of total serum bilirubin from 6 to 20 mg/dL. In this case phenobarbital treatment helps to lower bilirubin lever by more than 30%.
Hyperbilirubinemia, familial transient neonatal (also called breastfeedingjaundice) is associated with mutation(s) that alone do not lead to bilirubin level increase in female patients, but their children when breastfed develop from mild to severe hyperbilirubinemia by receiving steroidal substances (with milk) inhibiting glucuronidation of unconjugated bilirubin that may lead to jaundice and even kernicterus.
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^Strassburg CP, Manns MP, Tukey RH (April 1998). "Expression of the UDP-glucuronosyltransferase 1A locus in human colon. Identification and characterization of the novel extrahepatic UGT1A8". J. Biol. Chem.273 (15): 8719–26. doi:10.1074/jbc.273.15.8719. PMID9535849.