UDP glucuronosyltransferase 1 family, polypeptide A1

UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an is_associated_with::enzyme that in humans is encoded by the UGT1A1 is_associated_with::gene.

UGT-1A is a is_associated_with::uridine diphosphate glucuronyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the is_associated_with::glucuronidation pathway that transforms small lipophilic molecules, such as is_associated_with::steroids, is_associated_with::bilirubin, is_associated_with::hormones, and is_associated_with::drugs, into is_associated_with::water-soluble, excretable is_associated_with::metabolites.

Gene
The UGT1A1 gene is part of a complex locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternate first is_associated_with::exons followed by four common exons. Four of the alternate first exons are considered is_associated_with::pseudogenes. Each of the remaining nine is_associated_with::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. Over 100 is_associated_with::genetic variants within the UGT1A1 gene have been described, some of which confer increased, reduced or inactive enzymatic activity. The UGT nomenclature committee has compiled a list of these variants, naming each with a * symbol followed by a number.

Clinical significance
is_associated_with::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:
 * is_associated_with::Gilbert syndrome (GS) can be caused by a variety of genetic changes, but in Caucasian and African-American populations, it is most commonly associated with the UGT1A1*28 is_associated_with::allele (rs8175347), a is_associated_with::homozygous 2-bp insertion (TA) mutation of the is_associated_with::TATA box is_associated_with::promoter region of the is_associated_with::UGT1A1 gene. This polymorphism impairs proper transcription of UGT1A1 gene, resulting in decreased transcriptional activity of UGT1A1 by about 70%; the resulting reduced enzyme activity leads to the is_associated_with::hyperbilirubinemia characteristic of GS.  The *28 polymorphism occurs with a frequency of 26-31% in Caucasians and 42-56% of African-Americans. About 10-15% of these populations are homozygous for the *28 allele, but only 5% actually develop UGT1A1-associated is_associated_with::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 Asian and Pacific Islander populations, UGT1A1*28 is much less common, occurring at a frequency of approximately 9-16% in Asian populations and 4% of Pacific Islanders. In these populations, Gilbert's syndrome is more often due to is_associated_with::missense mutations in the coding region of the gene, such as UGT1A1*6 (is_associated_with::glycine to is_associated_with::arginine substitution at position 71 (G71R); rs4148323) A special is_associated_with::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 UGT1A1 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 UGT1A1 enzyme, which is still unable to catalyze the is_associated_with::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 UGT1A1 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%.
 * is_associated_with::Hyperbilirubinemia, familial transient neonatal (also called is_associated_with::breastfeeding is_associated_with::jaundice) 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 is_associated_with::steroidal substances (with milk) inhibiting glucuronidation of unconjugated bilirubin that may lead to jaundice and even is_associated_with::kernicterus.

Pharmacogenetics
Genetic variations within the UGT1A1 gene have also been associated with the development of certain drug toxicities. The UGT1A1*28 variant, the same is_associated_with::allele behind many cases of is_associated_with::Gilbert syndrome, has been associated with an increased risk for is_associated_with::neutropenia in patients receiving the chemotherapeutic drug is_associated_with::irinotecan, and the is_associated_with::U.S. Food and Drug Administration recommends on the irinotecan drug label that patients with the *28/*28 is_associated_with::genotype receive a lower starting dose of the drug. The *28 is_associated_with::allele has also shown associations with an increased risk for developing is_associated_with::diarrhea in patients receiving is_associated_with::irinotecan. The UGT1A1*6 variant, more common in Asian populations than the *28 variant, has also shown associations with the development of is_associated_with::irinotecan toxicities. Patients who are is_associated_with::heterozygous or is_associated_with::homozygous for the *6 is_associated_with::allele may have a higher risk for developing is_associated_with::neutropenia and is_associated_with::diarrhea as compared to those with the UGT1A1*1/*1 is_associated_with::genotype.