The UGT1A1 gene is part of a complex
locus that encodes several UDP-glucuronosyltransferases. The locus includes thirteen unique alternative 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.[7] Over 100
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
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:[8]
Gilbert syndrome (GS) can be caused by a variety of genetic changes, but in populations of European and African descent, it is most commonly associated with the UGT1A1*28
allele (
rs8175347), a
homozygous 2-
bpinsertion (
TA) mutation of the
TATA boxpromoter region of the
UGT1A1 gene.[8][9][10] 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
hyperbilirubinemia characteristic of GS.[8][9][11] The *28
polymorphism occurs with a frequency of 26-31% in White and 42-56% of African-Americans.[12] About 10-15% of these populations are homozygous for the *28 allele, but only 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.[8][9] 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.[12][13] In these populations, Gilbert's syndrome is more often due to
missense mutations in the coding region of the gene, such as UGT1A1*6 (
glycine to
arginine substitution at position 71 (G71R);
rs4148323) [8][9] 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).[8][9]
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
glucuronidation of bilirubin, which on the other hand makes phenobarbital treatment diagnostically relevant.[8][14]
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%.[8][15]
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.[8][16]
Pharmacogenetics
Genetic variations within the UGT1A1 gene have also been associated with the development of certain
drug toxicities. The UGT1A1*28
variant, the same
allele behind many cases of
Gilbert syndrome. The UGT1A1*28 has been associated with an increased risk for
neutropenia and
Diarrhea in patients receiving the chemotherapeutic drug
irinotecan[17][18] due to the insufficient excrete the active metabolite SN‐38, which primarily undergoes glucuronidation in livers.[19] The
U.S. Food and Drug Administration recommends on the irinotecan drug label that patients with the *28/*28
genotype receive a lower starting dose of the drug.[19][20] The *28
allele has also shown associations with an increased risk for developing
diarrhea in patients receiving
irinotecan.[17][18] The UGT1A1*6
variant, more common in Asian populations than the *28
variant, has also shown associations with the development of
irinotecan toxicities. Patients who are
heterozygous or
homozygous for the *6
allele may have a higher risk for developing
neutropenia and
diarrhea as compared to those with the UGT1A1*1/*1
genotype.[17][18]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
Innocenti F, Ratain MJ (2003). "Irinotecan treatment in cancer patients with UGT1A1 polymorphisms". Oncology (Williston Park, N.Y.). 17 (5 Suppl 5): 52–5.
PMID12800608.
Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development". Oncologist. 10 (2): 104–11.
doi:
10.1634/theoncologist.10-2-104.
PMID15709212.