Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: UGT1A1
SNOMEDCT: 27503000, 47444008, 68067009, 8933000; ICD10CM: E80.4;
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38): 2:233,760,270-233,773,300 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.1 | [Bilirubin, serum level of, QTL1] | 601816 | 3 | |
| [Gilbert syndrome] | 143500 | Autosomal recessive | 3 | |
| Crigler-Najjar syndrome, type I | 218800 | Autosomal recessive | 3 | |
| Crigler-Najjar syndrome, type II | 606785 | Autosomal recessive | 3 | |
| Hyperbilirubinemia, familial transient neonatal | 237900 | Autosomal dominant; Autosomal recessive | 3 |
Glucuronidation represents a major pathway that enhances the elimination of many lipophilic xenobiotics and endobiotics to more water-soluble compounds. UDP-glucuronosyltransferases (UGTs, or UDPGTs; EC 2.4.1.17) catalyze the addition of the glycosyl group from a nucleotide sugar to a small hydrophobic molecule (aglycone). UGT1A1 encodes the critically important bilirubin UGT (Ritter et al., 1992).
UGT1A Gene Complex
Several UGT1A enzymes, including UGT1A1, are encoded by the UGT1A gene complex on chromosome 2q37. The 5-prime region of the UGT1A complex contains 13 tandemly arrayed first exons, including 4 pseudo exons, that are linked to 4 common exons in the UGT1A 3-prime region. Each first exon has its own promoter element. The 9 viable first exons are independently spliced to the common exons 2 through 5 to generate 9 UGT1A transcripts with unique 5-prime ends and identical 3-prime ends. The N-terminal region encoded by each unique first exon determines acceptor substrate specificity, while the 246-amino acid C-terminal region encoded by the 4 common exons specifies interactions with the common donor substrate, UDP-glucuronic acid (Gong et al., 2001).
Each first exon is considered a unique gene linked to the 4 common exons in the UGT1A complex. For information on functional UGT1A proteins other than UGT1A1, see UGT1A3 (606428), UGT1A4 (606429), UGT1A5 (606430), UGT1A6 (606431), UGT1A7 (606432), UGT1A8 (606433), UGT1A9 (606434), and UGT1A10 (606435). The 4 UGT1A pseudogenes are designated UGT1A2P, UGT1A11P, UGT1A12P, and UGT1A13P.
For members of the UDP glycosyltransferase gene superfamily, Burchell et al. (1991) suggested and Mackenzie et al. (1997) recommended that the root UGT symbol be followed by an arabic number representing the family, followed by a letter designating the subfamily, and then another arabic number denoting the individual gene. Mackenzie et al. (1997) noted that the UGT1 complex contains at least 12 promoters/first exons that can be spliced and joined with common exons 2 through 5. In this nomenclature scheme, each first exon is regarded as a distinct gene. Mackenzie et al. (2005) provided a nomenclature update for the UGT gene superfamily.
By screening a liver cDNA library with a probe to a conserved transferase C-terminal sequence, followed by 5-prime RACE, Ritter et al. (1991) obtained cDNAs encoding UGT1A1 and UGT1A4 (606429), which they termed HUGBR1 and HUGBR2, respectively. Sequence analysis predicted that the 533-amino acid UGT1A1 protein shares with UGT1A4 66% sequence similarity in the N terminus, which contains potential N-linked glycosylation sites, and complete identity after codon 287. Northern blot analysis revealed expression of a 2.6-kb transcript in liver.
Wooster et al. (1991) determined the sequence of human liver UDP glucuronosyltransferases and concluded that the bilirubin UDP glucuronosyltransferases are derived from the same large gene as the phenol UGTs.
Using Northern blot analysis, Basu et al. (2004) detected tissue-specific expression of UGT1A1, UGT1A7 (606432), UGT1A8 (606433), UGT1A9 (606434), and UGT1A10 (606435). UGT1A1 was expressed highly in liver, moderately in regions of small intestine and rectum, and weakly in thyroid, spinal cord, trachea, uterus, and esophagus. In situ hybridization showed highest UGT1A1 expression in duodenal enterocytes, with progressively lower expression in mucosal layers of ileum and mucous-secreting goblet cells of colon.
Girard et al. (2007) stated that 9 UGT1A proteins with different N-terminal halves are produced by alternative splicing of 13 unique first exons to 4 common exons in the UGT1A gene complex. They showed that 9 additional UGT1A proteins are generated by alternative splicing resulting in inclusion of a novel common region exon, exon 5b. Girard et al. (2007) referred to the 9 original UGT1A proteins as 'isoform-1' and the 9 novel proteins as 'isoform-2.' UGT1A variants containing both exons 5A and 5B have the same ORFs as those containing only exon 5B, and thus produce isoform-2. The predicted isoform-2 proteins lack the C-terminal transmembrane domain encoded by exon 5A, but the 10 amino acids encoded by exon 5B contain a typical dilysine motif for endoplasmic reticulum retention. RT-PCR showed that all UGT1A splice variants were widely expressed in a tissue-specific manner. Exon 5B-containing transcripts were most often coexpressed with their respective exon 5A-containing transcripts, although there were exceptions. Western blot analysis of microsomes from human tissues detected UGT1A isoform-1 and -2 proteins of 55 and 45 kD, respectively. Both UGT1A1 isoforms were expressed in intestine, ileum, and jejunum microsomes, whereas only isoform-1 of UGT1A1 was expressed in liver microsomes, and only isoform-2 of UGT1A1 was expressed in kidney microsomes. Girard et al. (2007) stated that expression of UGT1A1 isoform-1 and -2 proteins also varied significantly among individuals. Endoglycosylation experiments with microsomes from transfected human embryonic kidney cells showed that both UGT1A isoforms were glycosylated. RT-PCR detected Ugt1a variants containing a homologous exon 5b in rat and monkey liver cDNA libraries, suggesting that the splicing mechanism that produces UGT1A isoform-2 is conserved.
UGT1A Gene Complex
The UGT1 gene contains at least 12 different promoters/first exons that are spliced to common exons 2 through 5, thus resulting in separate UGT1A forms with unique N termini and a conserved 246-amino acid C terminus Ritter et al. (1992). Each of these UGT1A forms has a distinctive substrate specificity (see Table 2 in Tukey and Strassburg, 2000).
Moghrabi et al. (1993) schematized the organization of the UGT1 gene complex, which involves constant and variable regions (Ritter et al., 1992).
Gong et al. (2001) completed description of the UGT1 gene complex locus, which spans some 218 kb. They provided evidence for 7 additional exons 1, specifying the UGT1A7 through UGT1A13P genes. Similar to the exon 1 that encodes UGT1A2P, exons 1 for the UGT1A11P through UGT1A13P genes are pseudo. The mRNA species encoded by the exons in the extended portion of the locus are primarily extrahepatic, with extensive distribution in the gastrointestinal tract.
Girard et al. (2007) identified an additional UGT1A common region exon, exon 5b, between exons 4 and 5A.
UGT1A Gene Complex
Harding et al. (1989, 1990) mapped the human phenol UDP-glucuronosyltransferase, which they termed GNT1, to chromosome 2. By human/rodent somatic cell hybridization, Moghrabi et al. (1992) mapped the gene encoding the human phenol and bilirubin UDP-glucuronosyltransferases (UGT1A subfamily) to chromosome 2. By in situ hybridization, van Es et al. (1993) mapped the gene to chromosome 2q37.
Classic breeding studies in Gunn rats suggested that bilirubin UGT and phenol UGT genes are linked on the same chromosome (Nagai et al., 1988). By study of recombinant inbred mice strains, Miles et al. (1991) mapped the phenol UGT gene in the mouse, Ugt1, to chromosome 1 in a region of homology to human chromosome 2. By linkage studies using restriction fragment length variations (RFLVs) detected in the bilirubin UDP-glucuronosyltransferase gene by means of a rat cDNA probe, Sato et al. (1992) likewise mapped the gene to mouse chromosome 1.
Functional analysis by Ritter et al. (1991) showed that UGT1A1 had glucuronidating activity.
In a review of the UGTs, Tukey and Strassburg (2000) indicated that UGT1A1 is the only isoform with bilirubin as its preferred substrate. UGT1A1 also has moderate activity on simple phenols, flavones, and C18 steroids. It has low activity with complex phenols and coumarins.
By Northern blot analysis, Strassburg et al. (1997) showed that UGT1A1, as well as other liver UGTs, including UGT1A3 (606428), UGT1A4 (606429), and UGT1A9 (606434), but not UGT1A6 (606431), are downregulated in malignant hepatocellular carcinoma.
Because there is an inverse relationship between serum bilirubin concentrations and the risk of coronary artery disease, Lin et al. (2003) carried out a genomewide scan in a Framingham Heart Study. Their study sample consisted of 330 families with 1,394 sib pairs, 681 cousin pairs, and 89 avuncular pairs. Using variance-component methods, the heritability was estimated to be 49% +/- 6%, and the genome scan demonstrated significant evidence of linkage of serum bilirubin to chromosome 2q, with a lod score of 3.8 at location 243 cM. The peak multipoint lod score is located 1 cM away from the UGT1A1 gene. Lin et al. (2003) concluded that UGT1A1 may be a major gene controlling serum bilirubin levels in the population.
Basu et al. (2004) showed that UGT1A1, UGT1A7, UGT1A8, UGT1A9, and UGT1A10 metabolized a broad range of chemicals, predominantly flavonoids, anthraquinones, hydrocarbons, and simple phenols. They also exhibited different pH optima according to the particular substrate and differed in their responses to high substrate concentrations. UGT1A1 was predominantly active at pH 6.4.
Girard et al. (2007) showed that all UGT1A isoform-2 proteins were enzymatically inactive against classical UGT1A substrates when using UDP-glucuronic acid as cosubstrate. However, glycosyltransferase activity of the isoform-1 proteins of UGT1A1, UGT1A7, UGT1A8, and UGT1A9 was significantly reduced when they were coexpressed with their respective isoform-2 protein. Girard et al. (2007) concluded that UGT1A isoform-2 proteins act as negative modulators of the active UGT1A isoform-1 proteins.
Zahreddine et al. (2014) identified a novel form of drug resistance to ribavirin and Ara-C, and observed that the GLI1 (165220) and UGT1A families of enzymes are elevated in resistant cells. UGT1As add glucuronic acid to many drugs, modifying their activity in diverse tissues. GLI1 alone is sufficient to drive UGT1A-dependent glucuronidation of ribavirin and Ara-C, and thus drug resistance. Resistance is overcome by genetic or pharmacologic inhibition of GLI1, revealing a potential strategy to overcome drug resistance in some patients.
Serum Level of Bilirubin Quantitative Trait Locus
Johnson et al. (2009) combined results from 3 genomewide association studies (Framingham Heart Study, Rotterdam Study, and AGES-Reykjavik) to assess genetic factors affecting serum bilirubin levels (601816) in 9,464 individuals. Metaanalysis showed strong replication of a genetic influence at the UGT1A1 locus for a G-T transversion rs6742078 (191740.0025; combined p value less than 5.0 x 10(-324)). In a subset of 490 individuals with UGT1A1*28 (191740.0011) and rs6742078 genotypes available, they found the markers to be in high linkage disequilibrium, suggesting the signal may be attributed to the UGT1A1*28 polymorphism. The rs6742078 variant in the UGT1A1 gene explained 18% of the variation in total serum bilirubin levels.
Suhre et al. (2011) reported a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with nontargeted metabolomics. They identified 37 genetic loci associated with blood metabolite concentrations, of which 25 showed effect sizes that were unusually high for GWAS and accounted for 10 to 60% differences in metabolite levels per allele copy. These associations provided new functional insights for many disease-related associations that had been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn disease. Suhre et al. (2011) identified rs887829 in the UGT1A gene as associated with bilirubin/oleoylcarnitine ratio with a p value of 2.9 x 10(-74).
Inherited Disorders of Unconjugated Hyperbilirubinemia
Mutations in the UGT1A1 gene are responsible for both type I and type II Crigler-Najjar syndromes (218800, 606785) as well as for the more common mild hyperbilirubinemia known as Gilbert syndrome (143500) (Kadakol et al., 2000). Patients with type I do not respond to phenobarbital treatment and only traces of bilirubin glucuronides can be found in their bile. Both Crigler-Najjar syndrome type II and Gilbert syndrome patients have reduced bilirubin transferase activity and are responsive to phenobarbital administration. Mutations in UGT1A1 are also responsible for some cases of breastfeeding jaundice (237900), which may be an infantile and inducible phenotype of Gilbert syndrome (Maruo et al., 2000).
In a patient with Crigler-Najjar syndrome type I, Ritter et al. (1992) identified a homozygous deletion in the UGT1A1 gene (191740.0001). The patient was born of consanguineous parents.
Moghrabi et al. (1993) identified a homozygous mutation in the UGT1A1 gene (191740.0004) in an 11-month-old male patient, born of consanguineous Pakistani parents, with Crigler-Najjar syndrome type I. The patient had total absence of all phenol/bilirubin UGT proteins and their activities in liver homogenate by enzymologic and immunochemical analysis.
Seppen et al. (1994) showed that the 2 types of Crigler-Najjar syndrome could be discriminated on the basis of expression of mutant cDNA in COS cells. All type I patients examined had completely inactive enzymes; the patients with type II had only partially inactivated enzyme. In one type II patient, there was 4.4% residual activity and in a second, 38% residual activity.
In affected members of 2 presumably unrelated Japanese families with Gilbert syndrome, Koiwai et al. (1995) identified a heterozygous mutation in the UGT1A gene (191740.0010). Expression studies in COS cells demonstrated approximately 14% of normal UGT activity, whereas enzymatic activity in the patient was approximately 30% of normal, suggesting a dominant-negative effect.
In 10 patients with Gilbert syndrome, Bosma et al. (1995) identified a homozygous 2-bp insertion (TA) in the TATAA element of the 5-prime promoter region of the UGT1A1 gene (191740.0011). Normally, an A(TA)6TAA element is present between nucleotides -23 and -38. All 10 patients were homozygous for the sequence A(TA)7TAA; this resulted in reduced expression of the gene. The (TA)7 allele was found to have a frequency of 40% among normal controls, indicating that it is a polymorphism. Thus, the promoter mutation appeared to be a necessary but not sufficient factor in Gilbert syndrome.
Yamamoto et al. (1998) identified mutations in the UGT1A1 gene (see, e.g., 191740.0010; 191740.0011) in 7 Japanese patients from 5 unrelated families with Crigler-Najjar syndrome type II.
Maruo et al. (2000) identified mutations in the UGT1A1 gene in patients with transient familial neonatal hyperbilirubinemia; some of the same mutations (e.g., 191740.0011) had been found in patients with Gilbert syndrome.
Petit et al. (2005) described paternal isodisomy for chromosome 2 as the cause of Crigler-Najjar syndrome type I. The affected child had a homozygous trinucleotide deletion in exon 1 resulting in the deletion of 1 of the 2 adjacent phenylalanine residues at position 170 or 171 of the protein (191740.0006). The father was heterozygous for the mutation. The father and child were both homozygous for the wildtype allele A(TA)6TAA in the promoter of the UGT1A1 gene. The mother had no mutation in the coding region of the UGT1A1 gene and was homozygous for the A(TA)7TAA mutant allele.
Petit et al. (2006) identified 15 different mutations, including 4 novel mutations, in the UGT1A1 gene among 13 patients with Crigler-Najjar syndrome type II.
Strassburg (2008) provided a review of the role of UGT1A1 variants in drug metabolism and noted that the variation of glucuronidation in patients with Gilbert syndrome impacts drug therapy, particularly with drugs that have a narrow therapeutic spectrum.
During a clinical trial of tocilizumab, Lee et al. (2011) identified 2 patients with elevated alanine aminotransferase (ALT) and total bilirubin, which in the absence of a mechanistic explanation predict increased risk of severe liver damage from pharmaceuticals (Hy's law). Both patients were homozygous for UGT1A1*28 (191740.0011), associated with Gilbert syndrome, and UGT1A1*60 alleles (rs4124874). UGT1A1*28 and 3 additional single-nucleotide polymorphisms (SNPs) showed odds ratios greater than 25 for associations with elevated bilirubin. Lee et al. (2011) concluded that the presence of rs6742078 (191740.0025) accounted for 32% of the total variance in bilirubin (p = 2.2 x 10(-53)). Since these elevations in bilirubin occurring with tocilizumab are not associated with hepatotoxicity, Lee et al. (2011) suggested the value of genotyping in the clinical trial setting.
Based on more than 50 UGT1A1 disease-causing mutations, Kadakol et al. (2000) presented a correlation of structure to function of UGT1A1. A common insertion mutation of the TATAA element upstream of UGT1A1 (191740.0011) results in a reduced level of expression. Homozygosity for this variant promoter is required for Gilbert syndrome, but is not sufficient for manifestation of hyperbilirubinemia, which is partly dependent on the rate of bilirubin production. Several structural mutations of UGT1A1, e.g., G71R (191740.0016), had been reported to cause mild reduction of UGT activity toward bilirubin, consistent with Gilbert syndrome. When the normal allele of a heterozygote carrier for a Crigler-Najjar-type structural mutation contains a Gilbert-type promoter, intermediate levels of hyperbilirubinemia may be observed, consistent with the diagnosis of Crigler-Najjar syndrome type II. Mackenzie et al. (1997) stated that more than 40 different deleterious mutations distributed both in the unique and common exons of the UGT1A1 gene had been found in Crigler-Najjar syndrome types I and II.
Kadakol et al. (2001) reported 4 families with unconjugated hyperbilirubinemia. In one family, 2 infants compound heterozygous for the promoter mutation and a structural mutation of the UGT1A1 gene (191740.0020) presented with neonatal hyperbilirubinemia sufficiently severe to cause kernicterus. In another family, compound heterozygosity for the promoter mutation and a missense mutation presented with mild hyperbilirubinemia. In a third family, homozygosity for both the promoter mutation and a missense mutation (191740.0021) produced Crigler-Najjar syndrome type II.
Sugatani et al. (2002) described a -3263T-G polymorphism in the phenobarbital response enhancer module (PBREM) in the UGT1A1 promoter with a frequency of 0.17 in the Japanese population. The polymorphism reduced transcriptional activity to 60% of normal. As the study by Ueyama et al. (1997) suggested that A(TA)7TAA alone is not the major cause of Gilbert syndrome and might be genetically linked to an unidentified defect, Maruo et al. (2004) tested the linkage of the 2 polymorphic mutations in 11 Caucasians and 12 Japanese patients who were homozygous for A(TA)7TAA. All 23 patients were also homozygous for the previously described polymorphism, which the authors referred to as T-3279G, indicating that -3263T-G and A(TA)7TAA were linked. Maruo et al. (2004) concluded that the decrease in transcription caused by both mutations together may be essential to Gilbert syndrome.
Severe toxicity is commonly observed in cancer patients receiving irinotecan (CPT-11). UGT1A1 catalyzes the glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Innocenti et al. (2004) found that grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients) compared with 6/7 (3 of 24 patients) and 6/6 (0 of 29 patients) (P = 0.001). The relative risk of grade 4 neutropenia was 9.3 for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels were significantly higher in patients with grade 4 neutropenia compared to those without grade 4 neutropenia. The -3156G-A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. It was suggested that the -3156G-A variant may be a better predictor of UGT1A1 status than the previously reported TA indel genotypes.
Kaniwa et al. (2005) investigated ethnic differences in genetic polymorphisms in UGT1A1 among African Americans, Caucasians, and Japanese using samples obtained from 150 individuals for each population. Seven polymorphisms including 3 SNPs in the 3-prime untranslated region of exon 5 were genotyped. Frequency of haplotypes in the 3 populations were compared. Differences in haplotype distribution patterns among the 3 populations suggested the possibility of ethnic differences in toxicity profiles of drugs detoxicated by UGT1A1. A novel SNP, 686C-T (P229L), was found in an African American. The intrinsic clearance of SN-38 by P229L UGT1A1 expressed in COS-1 cells was about 3% of wildtype. The results of Western blotting and real-time RT-PCR suggested that the low glucuronidation activity of the variant was partly due to its low stability. Kaniwa et al. (2005) suggested that the variant 686C-T may cause high toxicity during CPT-11 therapy or hyperbilirubinemia in patients.
Akaba et al. (1998) reported that the G71R (191740.0016) mutation of the UGT1 gene, which in homozygous state causes Gilbert syndrome, is prevalent among Japanese, Korean, and Chinese populations, with a gene frequency of 0.13, 0.23, and 0.23, respectively. Akaba et al. (1999) showed that neonates carrying the G71R mutation have significantly increased bilirubin levels at days 2 to 4 in a gene dose-dependent manner and that the frequency of this mutation was significantly higher in the neonates who required phototherapy than in those who did not. They suggested that the G71R mutation contributes to the high incidence of neonatal hyperbilirubinemia in Japanese.
Hagiwara et al. (1991) used a 5-prime EcoRI fragment of a cDNA cloned by Jackson et al. (1987) to map what they presumed to be the bilirubin glucuronosyltransferase. They concluded that the gene is located on chromosome 1 by study of sorted chromosomes and narrowed the assignment to 1q21-q23 by high resolution in situ hybridization. However, Burchell (1991), who without his knowledge or consent was named as an author, reported that the probe used (prepared in his laboratory) was not specific for bilirubin UDPGT but rather was a relatively nonspecific probe for 6-alpha-hydroxy bile acid UGT. Both the bilirubin UGTs and phenol UGTs are encoded by UGT1.
Irinotecan (CTP-11) is an antitumor agent that was approved in 1997 for use in patients with metastatic colorectal cancer refractory to 5-fluorouracil therapy. Irinotecan is a semisynthetic analog of the cytotoxic alkaloid camptothecin (CPT), which is obtained from the oriental tree Camptotheca acuminata. Irinotecan is an inhibitor of the topoisomerase-1 enzyme (TOP1; 126420). It is biotransformed by tissue and serum carboxyl esterases into the inactive metabolite SN-38 (7-ethyl-10-hydroxycamptothecin), which has a 100- to 1,000-fold higher antitumor activity than irinotecan. SN-38 is glucuronidated by hepatic UGTs. The major dose-limiting toxicity of irinotecan therapy is diarrhea, which is believed to be secondary to the biliary excretion of SN-38, the extent of which is determined by SN-38 glucuronidation. Iyer et al. (1998) undertook a study to identify the specific isoform of UGT involved in SN-38 glucuronidation. In vitro glucuronidation of SN-38 was screened in hepatic microsomes from normal rats, normal humans, Gunn rats, and patients with Crigler-Najjar type I syndrome (218800). A wide intersubject variability in the in vitro SN-38 glucuronide formation rates was found in humans. Gunn rats and Crigler-Najjar patients lacked SN-38 glucuronidating activity. A significant correlation was observed between SN-38 and bilirubin glucuronidation, whereas there was a poor relationship between para-nitrophenol and SN-38 glucuronidation. In HK293 cells, intact SN-38 glucuronidation was observed only in cells transfected with the UGT1A1 isozyme. These findings indicated a genetic predisposition to the metabolism of irinotecan, suggesting that patients with low UGT1A1 activity, such as those with Gilbert syndrome, may be at increased risk for irinotecan toxicity.
The Gunn rat is an excellent animal model of type I Crigler-Najjar syndrome, exhibiting deletion of a single guanosine (G) within the Ugt1a1 gene. The defect results in a frameshift and a premature stop codon, absence of enzyme activity, and hyperbilirubinemia. Kren et al. (1999) showed permanent correction of the Ugt1a1 genetic defect in Gunn rat liver with site-specific replacement of the absent G residue at nucleotide 1206 by using an RNA/DNA oligonucleotide designed to promote endogenous repair of genomic DNA. The chimeric oligonucleotide was either complexed with polyethylenimine or encapsulated in anionic liposomes, administered intravenously, and targeted to the hepatocyte via the asialoglycoprotein receptor (ASGR1; 108360). G insertion was determined by PCR amplification, colony lift hybridizations, restriction endonuclease digestion, and DNA sequencing, and confirmed by genomic Southern blot analysis. DNA repair was specific, efficient, and stable throughout the 6-month observation period, and was associated with reduction of serum bilirubin levels.
Findlay et al. (2000) reported that the predominant thyroid hormone released from the thyroid gland, T4, and the inactive rat T3 were glucuronidated by cloned expressed bilirubin UGT1A1 and also phenol UGT1A9. Results from Crigler-Najjar microsomal samples indicated that UGT1A1 was the main contributor to thyroid hormone glucuronidation in the liver, with rat T3 being the preferential substrate. In kidney microsomes, thyroid hormone glucuronidation was more complex, suggesting that more than just the UGT1A9 isoform may be involved. Bioactive T3 was not significantly glucuronidated by these isoforms and other UGTs, and sulfotransferases may have been involved.
Nguyen et al. (2008) found that Ugt1 -/- mice developed extreme jaundice within 8 hours of birth, and all Ugt1 -/- mice died within 2 weeks. In Ugt1 -/- mice, serum levels of unconjugated bilirubin were 40- to 60-times higher than that of Ugt1 +/- or wildtype mice, which is comparable to that found in patients with Crigler-Najjar type I disease. Ugt2-dependent glucuronidation activity was unaffected. Microarray analysis showed that loss of Ugt1 in liver altered the expression of more than 350 genes at least 1.5-fold. Genes that were affected included those involved in cell cycle regulation, kinase regulation, fatty acid and pyrimidine metabolism, and steroid metabolism.
This variant has been designated UGT1A1*2 (MacKenzie et al., 1997).
In a patient with Crigler-Najjar syndrome type I (218800), born of consanguineous parents, Ritter et al. (1992) identified a homozygous 13-bp deletion in exon 2 of the UGT1A1 gene. Both parents were heterozygous for the allele, which was initially referred to as UGT1*FB for the initials of the patient. The mutation was predicted to result in the synthesis of a severely truncated bilirubin transferase isozyme that lacked a highly conserved sequence in the C terminus and the characteristic membrane (endoplasmic reticulum)-anchoring segment of the protein molecule.
This variant has been designated UGT1A1*3 (Mackenzie et al., 1997).
In a patient with type I Crigler-Najjar syndrome (218800) and deficiency of both bilirubin-UGT and phenol-UGT activities in the liver, Bosma et al. (1992) found a C-to-T transition in exon 4 of the UGT1A1 gene, resulting in a ser376-to-phe (S376F) substitution.
Erps et al. (1994) identified a homozygous S376F substitution in 2 affected first cousins from a consanguineous family with Crigler-Najjar syndrome type I. The mutation was present in all UGT1-encoded UDPGTs, including the primary bilirubin UDPGT isoform.
This variant has been designated UGT1A1*5 (Mackenzie et al., 1997).
In a patient with type I Crigler-Najjar syndrome (218800), Bosma et al. (1992) found a C-to-T transition 6 bp upstream from the 3-prime end of exon 2 of the UGT1A1 gene, resulting in a gln331-to-ter (Q331X) substitution. Although the splice sites surrounding exon 2 were normal, mRNA analysis showed a 132-nucleotide deletion corresponding to the skipping of exon 2 in this patient. The relationship of the Q331R mutation and exon 2 skipping was unclear. A mutation involving the same codon (Q331R; 191740.0005) was identified in a patient with type II Crigler-Najjar syndrome (606785).
This variant has been designated UGT1A1*10 (Mackenzie et al., 1997).
In an 11-month-old male patient, with Crigler-Najjar syndrome type I (218800), born of consanguineous Pakistani parents, Moghrabi et al. (1993) identified a homozygous C-to-T transition in exon 3 of the UGT1A1 gene, resulting in an arg341-to-ter (R341X) substitution. The patient had total absence of all phenol/bilirubin UGT proteins and their activities in liver homogenate by enzymologic and immunochemical analysis.
Maruo et al. (2003) reported a Chinese girl with Crigler-Najjar syndrome type I, born of consanguineous parents, who was homozygous for the R341X mutation, which resulted from a 1021C-T transition. Family members heterozygous for the R341X mutation were asymptomatic. However, 3 family members with Gilbert syndrome (143500) were found to be compound heterozygous for R341X and a complex allele containing 2 mutations (P229Q; 191740.0010 and A(TA)7TAA; 191740.0011).
This variant has been designated UGT1A1*9 (Mackenzie et al., 1997).
In a 72-year-old Irish man with Crigler-Najjar syndrome type II (606785), born of consanguineous parents, Moghrabi et al. (1993) identified a homozygous A-to-G transition in exon 2 of the UGT1A1 gene, resulting in a gln331-to-arg (Q331R) substitution. The patient was one of the brothers reported by Gollan et al. (1975). The diagnosis was initially made at the age of 55 years on the basis of reduction in serum bilirubin levels upon treatment with phenobarbitone. Despite the lack of phenobarbital therapy until the age of 55, he exhibited no signs of intellectual impairment; however, a slight bilateral intention tremor and some nonspecific EEG abnormalities were detected. A mutation resulting in a premature stop codon at Q331 had been identified in a patient with type I Crigler-Najjar syndrome (218800; see Q331X, 191740.0003).
This variant has been designated UGT1A1*13 (Mackenzie et al., 1997).
In a patient with Crigler-Najjar type I (218800), Ritter et al. (1993) identified a deletion of a phenylalanine codon at position 170 in exon 1 of the UGT1A1 gene, abolishing a conserved diphenylalanine. The structure of the wildtype enzyme compared to that of the mutant indicated that hydrophobic properties at the active center are critical for metabolizing the lipophile-like substrate.
Rosatelli et al. (1997) identified the phe170del mutation in 5 Sardinian patients with Crigler-Najjar syndrome type I; 2 of the 5 were sibs. Whereas the other 3 patients were homozygous for the phe170del mutation, the sibs were compound heterozygotes for this mutation and a 470insT mutation (191740.0012). All but 2 heterozygotes for the phe170del mutation showed normal serum bilirubin levels; these 2 subjects were compound heterozygous for the sequence variation A(TA)7TAA in the promoter region of the UGT1A gene (191740.0011).
Petit et al. (2005) described paternal isodisomy for chromosome 2 as the cause of Crigler-Najjar type I syndrome. The affected child had a homozygous trinucleotide deletion in exon 1 resulting in the deletion of 1 of the 2 adjacent phenylalanine residues at position 170 or 171 of the protein and was homozygous for the wildtype allele A(TA)6TAA.
This variant has been designated UGT1A1*11 (Mackenzie et al., 1997).
In a 7-year-old girl with Crigler-Najjar syndrome type I (218800), born of consanguineous parents, Erps et al. (1994) identified a homozygous G-to-A transition in the UGT1A1 gene, resulting in a gly309-to-glu (G309E) substitution. The unaffected parents and 1 sib were heterozygous for the mutation.
This variant has been designated UGT1A1*25 (Mackenzie et al., 1997).
In a 1-year-old boy with type I Crigler-Najjar syndrome (218800), Aono et al. (1994) identified a homozygous 840C-A transversion in exon 1 of the UGT1A1 gene, resulting in a cys280-to-ter (C280X) substitution. The unaffected parents and elder brother were heterozygous for the mutation.
This variant has been designated UGT1A1*27 (Mackenzie et al., 1997).
In affected members of 2 presumably unrelated Japanese families with Gilbert syndrome (143500), Koiwai et al. (1995) identified a heterozygous 686C-A transversion in the UGT1A gene, resulting in a pro229-to-gln (P229Q) substitution. Expression studies in COS cells demonstrated approximately 14% of normal UGT activity, whereas enzymatic activity in the patient was approximately 30% of normal, suggesting a dominant-negative effect. Since, according to Peters et al. (1984), UGT exists as a tetramer on the luminal surface of the endoplasmic reticulum, the reduced level of UGT activity in the patient with Gilbert syndrome may be explained by the random formation of complexes of mutated UGT subunits and normally active UGT subunits on the endoplasmic reticulum.
In a patient with Crigler-Najjar syndrome type II (606785), Yamamoto et al. (1998) identified a complex genotype consisting of heterozygosity for the P229Q mutation and homozygosity for a 2-bp insertion mutation (191740.0011).
Udomuksorn et al. (2007) found that the P229Q mutant protein reduced the in vitro clearance for total bilirubin glucuronidation by 70% by increasing Km and decreasing Vmax. The magnitude of decreases in clearance for other substrates varied according to substrate.
This variant has been designated UGT1A1*28 (Mackenzie et al., 1997).
In 10 patients with Gilbert syndrome (143500), Bosma et al. (1995) identified a homozygous 2-bp insertion (TA) in the TATAA element of the 5-prime promoter region of the UGT1A1 gene. Normally, an A(TA)6TAA element is present between nucleotides -23 and -38. All 10 patients were homozygous for the sequence A(TA)7TAA; this resulted in reduced expression of the gene. The (TA)7 allele was found to have a frequency of 40% among normal controls, indicating that it is a polymorphism. Thus, the promoter mutation appeared to be a necessary but not sufficient factor in Gilbert syndrome.
Bosma et al. (1995) found that 2 related individuals with Crigler-Najjar syndrome type II (606785) who were homozygous for a structural mutation in the UGT1A1 gene (Bosma et al., 1993) were also both homozygous for the wildtype A(TA)6TAA allele. Among 10 family members who were heterozygous for the coding mutation, the other allele contained the (TA)7 element in 6 and the (TA)6 element in 4. The 6 heterozygotes with the promoter abnormality had significantly higher serum bilirubin values than the 4 with the normal TATAA element.
Kaplan et al. (1997) found that neonates with G6PD Mediterranean deficiency (305900.0006) who were heterozygous or homozygous for the variant (TA)7 UGT1A1 allele had a higher incidence of hyperbilirubinemia than corresponding controls. Among those normal for G6PD, the UGT1A1 polymorphism had no significant effect. Neither G6PD deficiency nor the variant UGT1A1 promoter alone increased the incidence of hyperbilirubinemia, but in combination both did. This gene interaction illustrated the paradigm of interaction of benign genetic polymorphisms in the causation of disease.
Beutler et al. (1998) described this variant in the promoter of the UGT1A1 gene as responsible for most cases of Gilbert syndrome.
In a patient with Crigler-Najjar syndrome type II, Yamamoto et al. (1998) identified an usual genotype consisting of heterozygosity for a P229Q mutation (191740.0010) and homozygosity for the 2-bp insertion mutation.
The (TA)7 mutation of the UGT1A1 gene had been associated with increased bilirubin levels in normal persons (Bosma et al., 1995), in those with heterozygous beta-thalassemia (Galanello et al., 1997) or G6PD deficiency (Sampietro et al., 1997), and with neonatal icterus in G6PD deficiency (Kaplan et al., 1997) and hereditary spherocytosis (Iolascon et al., 1998).
Beutler et al. (1998) examined the genotypes for the (TA)7 mutation in persons of Asian, African, and Caucasian ancestry. Although within the Caucasian ethnic group there was a strong correlation between promoter repeat number and bilirubin level, between ethnic groups they found that this relationship was inverse. Among people of African ancestry, there were, in addition to those with 6 and 7 repeats, also persons who had 5 or 8 repeats. Using a reporter gene they showed that there is an inverse relationship between the number of TA repeats and the activity of the promoter through the range of 5 to 8 TA repeats. An incidental finding was a polymorphism at nucleotide -106, tightly linked to the (TA)5 haplotype. Serum bilirubin levels are influenced by many factors, both genetic and environmental. Beutler et al. (1998) suggested that the unstable UGT1A1 polymorphism may serve to 'fine tune' the plasma bilirubin level within population groups, maintaining it at a high enough level to provide protection against oxidative damage, but at a level that is sufficiently low to prevent kernicterus in infants.
In addition to the known common UGT1A1 TATA alleles (TA6 and TA7), Monaghan et al. (1999) identified a novel TATA allele (TA5) in a neonate with very prolonged jaundice. Statistical analysis of TATA genotype distributions within a group of breastfed neonates revealed significant differences among the acute, prolonged, and very prolonged subgroups: the incidence of familial hyperbilirubinemia genotypes (7/7 and 5/7) was 5 times greater in very prolonged cases (31%) relative to acute cases (6%). Neonates with prolonged jaundice from family pedigrees were observed to demonstrate the Gilbert syndrome phenotype as children or young adults.
Kaplan et al. (2000) investigated whether the UGT promoter polymorphism would increase hyperbilirubinemia in direct Coombs-negative ABO (see 616093)-incompatible neonates, as seen in other combinations with this condition. Forty ABO-incompatible and 334 ABO-compatible controls had an allele frequency of 0.35 for the variant promoter gene. The incidence of hyperbilirubinemia was significantly higher only in the ABO-incompatible group who were also homozygous for the variant UGT promoter, compared with ABO-incompatible babies homozygous for the normal UGT promoter (43% vs 0.0; p of 0.02), and compared with ABO-compatible controls of all UGT genotypes combined (relative risk, 5.65; 95% CI, 2.23 to 14.31). Kaplan et al. (2000) concluded that Gilbert syndrome is a determining factor for neonatal hyperbilirubinemia in ABO incompatibility.
Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Sequencing of UGT1A1 revealed that 1 infant was a compound heterozygote for this TATA box variant and the G71R missense mutation (191740.0016).
Kadakol et al. (2001) found compound heterozygosity for the Gilbert-type promoter and a structural mutation of the UGT1A1 gene (191740.0020) in 18-month-old twins with severe neonatal hyperbilirubinemia resulting in kernicterus. They also found the promoter mutation in compound heterozygosity with a missense mutation resulting in mild hyperbilirubinemia. Homozygosity for both the Gilbert-type promoter and a missense mutation (191740.0021) resulted in Crigler-Najjar syndrome type II.
In a young girl with Crigler-Najjar syndrome type II, Labrune et al. (2002) found homozygosity for a (TA)8 polymorphism and an asn400-to-asp mutation (191740.0022).
In a study of 67 patients with sickle cell anemia (603903) in Brazil, Fertrin et al. (2003) found that TA6/TA7 heterozygotes and TA7/TA7 homozygotes had higher bilirubin levels; both groups had a higher probability of presenting symptomatic cholelithiasis (600803) than TA6/TA6 homozygotes, but this finding was only statistically significant in the TA6/TA7 heterozygotes.
Using a novel PCR method termed fluorescence resonance energy transfer (FRET), Borlak et al. (2000) reported the (TA)6 and (TA)7 UGT1A1 genotypes of 265 unrelated healthy individuals from southern Germany. Genotype distribution was 43:45:12 for (TA)6/(TA)6, (TA)6/(TA)7, and (TA)7/(TA)7, respectively. Serum total bilirubin levels increased with presence of the (TA)7 allele; median micromoles per liter were 12.0, 14.0, and 20.5, respectively, which was a statistically significant difference. Prevalence for the homozygous (TA)7 genotype was 12.4%. Borlak et al. (2000) emphasized the clinical importance of the UGT1A1 genotype and function of the enzyme, particularly for drug metabolism.
Roses (2004) pointed to an example of a mild adverse event with a clear genetic component that could be used as a model of the safe use of pharmacogenetics. Some patients in a trial of tranilast, a specific drug to retard coronary artery restenosis after surgery, under investigation by GlaxoSmithKline, developed hyperbilirubinemia. A screen for variants in candidate genes revealed that high levels of bilirubin were most common in patients who were homozygous for the 7-repeat UGT1A1 allele. Breaking the placebo- versus the drug-treated codes at the end of the trial showed that all 7-7 patients who developed hyperbilirubinemia received the drug, whereas none of the 7-7 patients treated with the placebo developed the adverse event. Several drug-treated patients with the 6-7 genotype also developed mildly elevated levels of bilirubin, but no treated or placebo patients with the 6-6 genotype became hyperbilirubinemic.
A study of UGT1A1 gene polymorphism by Edison et al. (2005) showed that the TA(7) variant was associated with hyperbilirubinemia in homozygous HbE patients homozygous for the hemoglobin E gene (HBE; 141900.0071). The role of the TA(7) polymorphism of UGT1A1 in the determination of jaundice and gallstones in hemoglobin E beta-thalassemia had been pointed out by Premawardhena et al. (2001) in studies from Sri Lanka. The same group (Premawardhena et al., 2003) studied the global distribution of length polymorphisms of the promoters of the UGT1A1 gene. They found that homozygosity for the TA(7) allele occurred in 10 to 25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurred at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations showed a much greater diversity of length alleles than other populations. These findings defined those populations with a high frequency of hemoglobin E beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gallbladder disease. Beutler et al. (1998) had suggested that the wide diversity in the frequency of the UGT1A1 promoter alleles might reflect a balanced polymorphism mediated through the protective effect of bilirubin against oxidative damage.
French et al. (2005) genotyped 126 children with newly diagnosed acute lymphoblastic leukemia at 16 well-characterized functional polymorphisms. The UGT1A1*28 polymorphism was a significant predictor of global gene expression, dividing patients based on their germline genotypes. Genes whose expression distinguished the TA 7/7 genotype from the other UGT1A1 genotypes included HDAC1 (601241), RELA (164014) and SLC2A1 (138140). Although UGT1A1 expression is concentrated in liver, it is involved in the conjugation (and thus transport, excretion, and lipophilicity) of a broad range of endobiotics and xenobiotics, which French et al. (2005) suggested could plausibly have consequences for gene expression in different tissues.
Using a competitive electrophoretic mobility shift assay (EMSA), Hsieh et al. (2007) demonstrated that mutant TA7 TATA-box-like sequence has reduced binding affinity for nuclear binding complex and for TATA-binding protein compared to wildtype TA6; quantitative EMSA showed that the binding affinity progressively decreases as the number of TA repeats in the TATA-box-like sequence increases. Hsieh et al. (2007) stated that this decrease in binding affinity causes the reduced promoter activity of mutant UGT1A1 compared to wildtype and explains the pathogenesis of Gilbert syndrome.
In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism and rs4148323 (191740.0016) (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the TA(7) allele was 0.134 in Han Chinese, 0.256 in the Uygur, and 0.277 in the Kazakh, which was lower than that reported for Caucasian populations (0.357 to 0.415; Beutler et al., 1998).
In 2 Sardinian sibs with Crigler-Najjar syndrome type I (218800), Rosatelli et al. (1997) found compound heterozygosity for the phe170del mutation (191740.0006) and a 1-bp insertion (470insT), which also resided in exon 1 of the UGT1A gene.
In a patient with Crigler-Najjar syndrome type I (218800), Gantla et al. (1998) identified a homozygous G-to-C transversion in the UGT1A1 gene at the splice donor site in the intron between exon 1 and exon 2. Both parents were heterozygous for the mutation.
In a patient with Crigler-Najjar syndrome type I (218800), Gantla et al. (1998) identified compound heterozygosity for 2 mutations in the UGT1A1 gene: a 145C-T transition in exon 1 resulting in a premature stop codon, and an A-to-G transition in the splice acceptor site of intron 3 (191740.0015). Each unaffected parent was heterozygous for one of the mutations.
See 191740.0014 and Gantla et al. (1998).
This variant is designated UGT1A1*6 and rs4148323.
In a Japanese girl with anorexia nervosa and Gilbert syndrome (143500), Maruo et al. (1999) identified a homozygous 211G-A transition in exon 1 of the UGT1A1 gene, resulting in a gly71-to-arg substitution (G71R). The parents were heterozygous for the mutation.
Akaba et al. (1998) reported that the G71R mutation of the UGT1A1 gene, which in homozygous state causes Gilbert syndrome, is prevalent among Japanese, Korean, and Chinese populations, with a gene frequency of 0.13, 0.23, and 0.23, respectively. Akaba et al. (1999) showed that neonates carrying the G71R mutation have significantly increased bilirubin levels (237900) at days 2 to 4 in a gene dose-dependent manner and that the frequency of this mutation was significantly higher in the neonates who required phototherapy than in those who did not. They suggested that the G71R mutation contributes to the high incidence of neonatal hyperbilirubinemia in Japanese.
Among 20 children with acute leukemia, Kimura et al. (1999) found 4 with intermittent unconjugated hyperbilirubinemia during the course of combined chemotherapy. The G71R mutation was detected in the 4 patients with hyperbilirubinemia but was not found in the other 16 patients. Two of the 4 were heterozygotes; one was a homozygote for the G71R mutation; and the other was a compound heterozygote for G71R and the TA insertion mutation in the TATA box (191740.0011).
Maruo et al. (2000) analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (serum bilirubin greater than 10 mg/dL at age 3 weeks to 1 month). When breastfeeding was stopped, the serum bilirubin levels began to decrease in all cases, but when breastfeeding was resumed, the serum bilirubin concentration again became elevated in some infants. Serum bilirubin levels normalized by the time the infants were 4 months old. Thus the infants had transient familial neonatal hyperbilirubinemia (237900). Sequencing of the UGT1A1 gene revealed that 8 infants were homozygous and 7 heterozygous for the G71R mutation. Another UGT1A1 missense mutation (191740.0017) was found in one of the G71R homozygotes, and an insertion in the TATA box of UGT1A1 (191740.0011) was found in one of the G71R heterozygotes.
Udomuksorn et al. (2007) found that the G71R mutant protein reduced the in vitro clearance for total bilirubin glucuronidation by 50% via a reduction in Vmax. The magnitude of decreases in clearance for other substrates varied according to substrate.
In a population-based study examining serum total bilirubin (BILIQTL1; 601816) in 3 Asian groups from Xinjiang, China, including 502 Kazakh herdsmen, 769 Uygur farmers, and 789 Han farmers, Lin et al. (2009) found a significant association with 2 polymorphisms in the UGT1A1 gene: the TA(n) repeat polymorphism (191740.0011) and rs4148323 (p = 2.05 x 10(-26) and p = 5.21 x 10(-16) respectively). The TA(7) allele and the A allele of rs4148323 were independently associated with increased total bilirubin levels. Combined, these SNPs could explain between 3.9 to 9.8% of the variance in these populations. The frequency of the A allele of rs4148323 for the Han, Uygur, and Kazakh populations was 0.211, 0.168, and 0.211, respectively, and could explain 9.8%, 4.5%, and 3.9%, respectively, of the total variation in bilirubin levels,
Sato et al. (2013) found that 56 (14%) of 401 Japanese neonates who were exclusively breastfed developed hyperbilirubinemia and required phototherapy. Neonates with a 10% or greater loss of body weight since birth had a significantly higher peak bilirubin level and incidence of hyperbilirubinemia, higher frequency of cesarean delivery, and shorter gestational period compared to those with less than 10% loss of body weight. Sex and body weight at birth were not significantly different between the 2 groups. UGT1A1 genotyping of the entire cohort showed that the frequency of the G71R polymorphism was 0.18 and was higher in neonates with body weight loss less than 10%. However, maximal body weight loss during the neonatal period was the only independent risk factor for the development of neonatal hyperbilirubinemia (odds ratio of 1.25). Although presence of the G71R variant was not a significant independent risk factor for neonatal hyperbilirubinemia overall, subgroup analysis revealed that G71R was a risk factor only in neonates with a 5% or greater maximal body weight loss, and the influence correlated with the degree of body weight loss. Sato et al. (2013) suggested that adequate feeding in the neonatal period may overcome the genetic predisposing factor of G71R to neonatal hyperbilirubinemia.
This variant is referred to as UGT1A1*7.
In an infant with transient familial neonatal hyperbilirubinemia associated with breastfeeding (237900), Maruo et al. (2000) found a heterozygous T-to-G transversion in exon 5 of the UGT1A1 gene, predicting the substitution of an aspartic acid for a tyrosine at amino acid 486 (Y486D). This infant was also heterozygous for the G71R mutation (191740.0016).
Udomuksorn et al. (2007) stated that homozygosity for the Y486D mutation is associated with Crigler-Najjar syndrome type II (606785).
Udomuksorn et al. (2007) found that the Y486D mutant protein had very low activity for in vitro clearance for total bilirubin glucuronidation. In addition, transfection of the Y486D mutation into UGT1A6 (606431) and UGT1A10 (606435) reduced their activity, indicating that the mutation may alter a common UGT1A active binding site.
In an infant with transient familial neonatal hyperbilirubinemia associated with breastfeeding (237900), Maruo et al. (2000) found a heterozygous C-to-A transversion within the enhancer region of the UGT1A1 gene. This mutation had previously been described by Ueyama et al. (1997).
In 6 Tunisian patients with Crigler-Najjar syndrome type I (218800), Francoual et al. (2002) identified a homozygous A-to-G transition in the UGT1A1 gene, resulting in a gln357-to-arg (Q357R) substitution. Furthermore, all 6 patients were homozygous for a TA insertion within the promoter of the UGT1A1 gene, thus resulting in TA7/TA7 homozygosity. All 12 parents were heterozygous for the Q357R mutation and the TA7 allele. The patients originated from different parts of Tunisia and were not related to each other. The findings suggested that the Q357R mutation in this group of patients was due to a founder effect.
Kadakol et al. (2001) identified a 1-bp deletion (1223delA) in the UGT1A1 gene in compound heterozygosity with a promoter mutation (191740.0011) in 2 girls with Crigler-Najjar syndrome type II (606785) who presented with severe neonatal hyperbilirubinemia resulting in kernicterus. Phenobarbital and phototherapy treatment resulted in a reduction of serum bilirubin concentrations.
In 2 girls with Crigler-Najjar syndrome type II (606785), Kadakol et al. (2001) identified a 524T-A transversion in the UGT1A1 gene, resulting in a leu175-to-gln (L175Q) substitution. Both girls were also homozygous for a UGT1A1 promoter variant (191740.0011).
Labrune et al. (2002) described a patient with Crigler-Najjar syndrome type II (606785) who was homozygous for a (TA)8 promoter polymorphism (191740.0011) and homozygous for a 1213A-G transition in exon 4 of the UGT1A1 gene, resulting in an asn400-to-asp (N400D) mutation. Both parents, who were first cousins, bore the same mutation in heterozygous state and had mild, fast-induced unconjugated hyperbilirubinemia compatible with the diagnosis of Gilbert syndrome (143500).
In 2 patients with Crigler-Najjar syndrome type II (606785), Seppen et al. (1996) identified homozygosity for a leu15-to-arg (L15R) substitution in the UGT1A1 gene. The mutation was predicted to disrupt the hydrophobic core of the signal peptide. Transfection studies in COS cells found equal expression of wildtype and mutant mRNA, but the mutant protein was expressed with 0.5% efficiency compared to the wildtype protein.
In COS cells transfected with the L15R mutation, Ohnishi and Emi (2003) found that the mutant protein did not relocate across the endoplasmic reticulum membrane and was degraded rapidly with a half-life of approximately 50 minutes, in contrast to the much longer half-life of approximately 12.8 hours for the wildtype protein. The findings demonstrated that the L15R mutant protein was rapidly degraded by the proteasome owing to its mislocalization in the cell.
Sugatani et al. (2002) identified a SNP, -3263T-G, in the UGT1A1 promoter, also known as the phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3). Functional studies showed that the polymorphism decreased transcriptional activity to approximately 62% of wildtype. Sugatani et al. (2002) identified the -3263T-G polymorphism in 21 of 25 patients with Gilbert syndrome (143500); 8 patients were homozygous and 13 were heterozygous. Five of the homozygotes were also homozygous for the (TA)7 mutation (191740.0011). Twelve of the polymorphism heterozygotes and 1 of the homozygotes were also heterozygous for the G71R mutation (191740.0016). Two of the 21 patients were compound heterozygotes for the -3263T-G polymorphism, the (TA)7 mutation, and the G71R mutation. Of the 4 individuals with Gilbert syndrome without the -3263T-G polymorphism, 3 had the G71R mutation (1 heterozygote and 2 homozygotes) and 1 had no detectable changes in the UGT1A1 gene. In the control group, 8 of 27 individuals had the -3263T-G polymorphism. The frequency of alleles carrying the polymorphism was significantly higher in the hyperbilirubinemic group than in the control group (0.58 vs 0.17, respectively). Plasma total bilirubin levels in the double heterozygotes were significantly higher than those with a single mutation or polymorphism, indicating that those individuals who are heterozygous for the -3263T-G polymorphism and for the G71R mutation are predisposed for hyperbilirubinemia in Gilbert syndrome.
Maruo et al. (2004), who referred to this polymorphism as T-3279G, studied 11 Caucasians and 12 Japanese patients with Gilbert syndrome and found that all 23 patients were homozygous for both A(TA)7TAA and -3263T-G, indicating that the 2 polymorphisms are linked. They suggested that the decrease of transcription caused by both mutations may be essential to the development of Gilbert syndrome.
Johnson et al. (2009) combined results from 3 genomewide association studies (Framingham Heart Study, Rotterdam Study, and AGES-Reykjavik) to assess genetic factors affecting serum bilirubin levels (601816) in 9,464 individuals. Metaanalysis showed strong replication of a genetic influence at the UGT1A1 locus for a G-T transversion rs6742078 (combined p value less than 5.0 x 10(-324)). In a subset of 490 individuals with UGT1A1*28 (191740.0011) and rs6742078 genotypes available, they found the markers to be in high linkage disequilibrium, suggesting the signal may be attributed to the UGT1A1*28 polymorphism. The rs6742078 variant in the UGT1A1 gene explained 18% of the variation in total serum bilirubin levels.
In 610 patients treated with tocilizumab plus methotrexate or another disease-modifying antirheumatic drug (DMARD), those homozygous for the variant allele at rs6742078 experienced an additional 0.43 mg/dl increase in maximum bilirubin, accounting for 32% of the total population variance in maximum change from baseline (p = 2.2 x 10(-53)).
Akaba, K., Kimura, T., Sasaki, A., Tanabe, S., Ikegami, T., Hashimoto, M., Umeda, H., Yoshida, H., Umetsu, K., Chiba, H., Yuasa, I., Hayasaka, K. Neonatal hyperbilirubinemia and mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene: a common missense mutation among Japanese, Koreans and Chinese. Biochem. Molec. Biol. Int. 46: 21-26, 1998. [PubMed: 9784835] [Full Text: https://doi.org/10.1080/15216549800203512]
Akaba, K., Kimura, T., Sasaki, A., Tanabe, S., Wakabayashi, T., Hiroi, M., Yasumura, S., Maki, K., Aikawa, S., Hayasaka, K. Neonatal hyperbilirubinemia and a common mutation of the bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese. J. Hum. Genet. 44: 22-25, 1999. [PubMed: 9929972] [Full Text: https://doi.org/10.1007/s100380050100]
Aono, S., Yamada, Y., Keino, H., Sasaoka, Y., Nakagawa, T., Onishi, S., Mimura, S., Koiwai, O., Sato, H. A new type of defect in the gene for bilirubin uridine 5-prime-diphosphate-glucuronosyltransferase in a patient with Crigler-Najjar syndrome type I. Pediat. Res. 35: 629-632, 1994. [PubMed: 7936809] [Full Text: https://doi.org/10.1203/00006450-199406000-00002]
Basu, N. K., Ciotti, M., Hwang, M. S., Kole, L., Mitra, P. S., Cho, J. W., Owens, I. S. Differential and special properties of the major human UGT1-encoded gastrointestinal UDP-glucuronosyltransferases enhance potential to control chemical uptake. J. Biol. Chem. 279: 1429-1441, 2004. [PubMed: 14557274] [Full Text: https://doi.org/10.1074/jbc.M306439200]
Beutler, E., Gelbart, T., Demina, A. Racial variability in the UDP-glucuronosyltransferase 1 (UGT1A1) promoter: a balanced polymorphism for regulation of bilirubin metabolism? Proc. Nat. Acad. Sci. 95: 8170-8174, 1998. [PubMed: 9653159] [Full Text: https://doi.org/10.1073/pnas.95.14.8170]
Borlak, J., Thum, T., Landt, O., Erb, K., Hermann, R. Molecular diagnosis of a familial nonhemolytic hyperbilirubinemia (Gilbert's syndrome) in healthy subjects. Hepatology 32: 792-795, 2000. [PubMed: 11003624] [Full Text: https://doi.org/10.1053/jhep.2000.18193]
Bosma, P. J., Goldhoorn, B., Oude Elferink, R. P. J., Sinaasappel, M., Oostra, B. A., Jansen, P. L. M. A mutation in bilirubin uridine 5-prime-diphosphate-glucuronosyltransferase isoform 1 causing Crigler-Najjar syndrome type II. Gastroenterology 105: 216-220, 1993. [PubMed: 8514037] [Full Text: https://doi.org/10.1016/0016-5085(93)90029-c]
Bosma, P. J., Roy Chowdhury, J., Bakker, C., Gantla, S., de Boer, A., Oostra, B. A., Lindhout, D., Tytgat, G. N. J., Jansen, P. L. M., Oude Elferink, R. P. J., Roy Chowdhury, N. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. New Eng. J. Med. 333: 1171-1175, 1995. [PubMed: 7565971] [Full Text: https://doi.org/10.1056/NEJM199511023331802]
Bosma, P. J., Roy Chowdhury, J., Huang, T.-J., Lahiri, P., Oude Elferink, R. P. J., Van Es, H. H. G., Lederstein, M., Whitington, P. F., Jansen, P. L. M., Roy Chowdhury, N. Mechanisms of inherited deficiencies of multiple UDP-glucuronosyltransferase isoforms in two patients with Crigler-Najjar syndrome, type I. FASEB J. 6: 2859-2863, 1992. [PubMed: 1634050] [Full Text: https://doi.org/10.1096/fasebj.6.10.1634050]
Burchell, B., Nebert, D. W., Nelson, D. R., Bock, K. W., Iyanagi, T., Jansen, P. L. M., Lancet, D., Mulder, G. J., Roy Chowdhury, J., Siest, G., Tephly, T. R., Mackenzie, P. I. The UDP glucuronosyltransferase gene superfamily: suggested nomenclature based on evolutionary divergence. DNA Cell Biol. 10: 487-494, 1991. [PubMed: 1909870] [Full Text: https://doi.org/10.1089/dna.1991.10.487]
Burchell, B. Personal Communication. Dundee, Scotland 12/1991.
Edison, E. S., Shaji, R. V., Srivastava, A., Chandy, M. Hyperbilirubinemia in homozygous HbE disease is associated with the UGT1A1 gene polymorphism. Hemoglobin 29: 189-195, 2005. [PubMed: 16114182] [Full Text: https://doi.org/10.1081/hem-200066314]
Erps, L. T., Ritter, J. K., Hersh, J. H., Blossom, D., Martin, N. C., Owens, I. S. Identification of two single base substitutions in the UGT1 gene locus which abolish bilirubin uridine diphosphate glucuronosyltransferase activity in vitro. J. Clin. Invest. 93: 564-570, 1994. [PubMed: 7906695] [Full Text: https://doi.org/10.1172/JCI117008]
Fertrin, K. Y., Melo, M. B., Assis, A. M., Saad, S. T. O., Costa, F. F. UDP-glucuronosyltransferase 1 gene promoter polymorphism is associated with increased serum bilirubin levels and cholecystectomy in patients with sickle cell anemia. (Letter) Clin. Genet. 64: 160-162, 2003. [PubMed: 12859413] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00113.x]
Findlay, K. A. B., Kaptein, E., Visser, T. J., Burchell, B. Characterization of the uridine diphosphate-glucuronosyltransferase-catalyzing thyroid hormone glucuronidation in man. J. Clin. Endocr. Metab. 85: 2879-2883, 2000. [PubMed: 10946897] [Full Text: https://doi.org/10.1210/jcem.85.8.6715]
Francoual, J., Rivierre, A., Mokrani, C., Khrouf, N., Gottrand, F., Myara, A., Le Bihan, B., Capel, L., Lindenbaum, A., Labrune, P. Crigler-Najjar syndrome type I in Tunisia may be associated with a founder effect related to the Q357R mutation within the UGT1 gene. Hum. Mutat. 19: 570-571, 2002. [PubMed: 11968090] [Full Text: https://doi.org/10.1002/humu.10064]
French, D., Wilkinson, M. R., Yang, W., de Chaisemartin, L., Cook, E. H., Das, S., Ratain, M. J., Evans, W. E., Downing, J. R., Pui, C.-H., Relling, M. V. Global gene expression as a function of germline genetic variation. Hum. Molec. Genet. 14: 1621-1629, 2005. [PubMed: 15857854] [Full Text: https://doi.org/10.1093/hmg/ddi170]
Galanello, R., Perseu, L., Melis, M. A., Cipollina, L., Barella, S., Giagu, N., Turco, M. P., Maccioni, O., Cao, A. Hyperbilirubinaemia in heterozygous beta-thalassaemia is related to co-inherited Gilbert's syndrome. Brit. J. Haemat. 99: 433-436, 1997. [PubMed: 9375768] [Full Text: https://doi.org/10.1046/j.1365-2141.1997.3703182.x]
Gantla, S., Bakker, C. T. M., Deocharan, B., Thummala, N. R., Zweiner, J., Sinaasappel, M., Roy Chowdhury, J., Bosma, P. J., Roy Chowdhury, N. Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1. Am. J. Hum. Genet. 62: 585-592, 1998. [PubMed: 9497253] [Full Text: https://doi.org/10.1086/301756]
Girard, H., Levesque, E., Bellemare, J., Journault, K., Caillier, B., Guillemette, C. Genetic diversity at the UGT1 locus is amplified by a novel 3-prime alternative splicing mechanism leading to nine additional UGT1A proteins that act as regulators of glucuronidation activity. Pharmacogenet. Genomics 17: 1077-1089, 2007. [PubMed: 18004212] [Full Text: https://doi.org/10.1097/FPC.0b013e3282f1f118]
Gollan, J. L., Huang, S. N., Billing, B., Sherlock, S. Prolonged survival in three brothers with severe type 2 Crigler-Najjar syndrome: ultrastructural and metabolic studies. Gastroenterology 68: 1543-1555, 1975. [PubMed: 805737]
Gong, Q.-H., Cho, J. W., Huang, T., Potter, C., Gholami, N., Basu, N. K., Kubota, S., Carvalho, S., Pennington, M. W., Owens, I. S., Popescu, N. C. Thirteen UDP-glucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics 11: 357-368, 2001. [PubMed: 11434514] [Full Text: https://doi.org/10.1097/00008571-200106000-00011]
Hagiwara, H., Takeda, K., Ikeda, H., Nakai, H., Burchell, B. Gene mapping of human bilirubin UDP-glucuronosyl transferase on 1q21-q23 by a cell sorter and in situ hybridization. Jpn. J. Hum. Genet. 36: 189-194, 1991.
Harding, D., Fournel-Gigleux, S., Jackson, M. R., Burchell, B. Cloning and substrate specificity of a human phenol UDP-glucuronosyltransferase expressed in COS-7 cells. Proc. Nat. Acad. Sci. 85: 8381-8385, 1988. [PubMed: 3141926] [Full Text: https://doi.org/10.1073/pnas.85.22.8381]
Harding, D., Jeremiah, S. J., Povey, S., Burchell, B. Phenol UDP-glucuronosyltransferase is coded by a gene on human chromosome 2. (Abstract) Cytogenet. Cell Genet. 51: 1011, 1989.
Harding, D., Jeremiah, S. J., Povey, S., Burchell, B. Chromosomal mapping of a human phenol UDP-glucuronosyltransferase, GNT1. Ann. Hum. Genet. 54: 17-21, 1990. [PubMed: 2108603] [Full Text: https://doi.org/10.1111/j.1469-1809.1990.tb00356.x]
Hsieh, T.-Y., Shiu, T.-Y., Huang, S.-M., Lin, H.-H., Lee, T.-C., Chen, P.-J., Chu, H.-C., Chang, W.-K., Jeng, K.-S., Lai, M. M. C., Chao, Y.-C. Molecular pathogenesis of Gilbert's syndrome: decreased TATA-binding protein binding affinity of UGT1A1 gene promoter. Pharmacogenet. Genomics 17: 229-236, 2007. [PubMed: 17496722] [Full Text: https://doi.org/10.1097/FPC.0b013e328012d0da]
Innocenti, F., Undevia, S. D., Iyer, L., Chen, P. X., Das, S., Kocherginsky, M., Karrison, T., Janisch, L., Ramirez, J., Rudin, C. M., Vokes, E. E., Ratain, M. J. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J. Clin. Oncol. 22: 1382-1388, 2004. [PubMed: 15007088] [Full Text: https://doi.org/10.1200/JCO.2004.07.173]
Iolascon, A., Faienza, M. F., Moretti, A., Perrotta, S., Miraglia del Giudice, E. UGT1 promoter polymorphism accounts for increased neonatal appearance of hereditary spherocytosis.(Letter) Blood 91: 1093 only, 1998. [PubMed: 9446675]
Iyer, L., King, C. D., Whitington, P. F., Green, M. D., Roy, S. K., Tephly, T. R., Coffman, B. L., Ratain, M. J. Genetic predisposition to the metabolism of irinotecan (CPT-11): role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J. Clin. Invest. 101: 847-854, 1998. [PubMed: 9466980] [Full Text: https://doi.org/10.1172/JCI915]
Jackson, M. R., McCarthy, L. R., Harding, D., Wilson, S., Coughtrie, M. W. H., Burchell, B. Cloning of a human liver microsomal UDP-glucuronosyltransferase cDNA. Biochem. J. 242: 581-588, 1987. [PubMed: 3109396] [Full Text: https://doi.org/10.1042/bj2420581]
Jansen, P. L. M., Mulder, G. J., Burchell, B., Bock, K. W. New developments in glucuronidation research: report of a workshop on 'glucuronidation, its role in health and disease.'. Hepatology 15: 532-544, 1992. [PubMed: 1531971] [Full Text: https://doi.org/10.1002/hep.1840150328]
Johnson, A. D., Kavousi, M., Smith, A. V., Chen, M.-H., Dehghan, A., Aspelund, T., Lin, J.-P., van Duijn, C. M., Harris, T. B., Cupples, L. A., Uitterlinden, A. G., Launer, L., Hofman, A., Rivadeneira, F., Stricker, B., Yang, Q., O'Donnell, C. J., Gudnason, V., Witteman, J. C. Genome-wide association meta-analysis for total serum bilirubin levels. Hum. Molec. Genet. 18: 2700-2710, 2009. [PubMed: 19414484] [Full Text: https://doi.org/10.1093/hmg/ddp202]
Kadakol, A., Ghosh, S. S., Sappal, B. S., Sharma, G., Roy Chowdhury, J., Roy Chowdhury, N. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum. Mutat. 16: 297-306, 2000. [PubMed: 11013440] [Full Text: https://doi.org/10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z]
Kadakol, A., Sappal, B. S., Ghosh, S. S., Lowenheim, M., Chowdhury, A., Chowdhury, S., Santra, A., Arias, I. M., Chowdhury, J. R., Chowdhury, N. R. Interaction of coding region mutations and the Gilbert-type promoter abnormality of the UGT1A1 gene causes moderate degrees of unconjugated hyperbilirubinaemia and may lead to neonatal kernicterus. (Letter) J. Med. Genet. 38: 244-249, 2001. [PubMed: 11370628] [Full Text: https://doi.org/10.1136/jmg.38.4.244]
Kaniwa, N., Kurose, K., Jinno, H., Tanaka-Kagawa, T., Saito, Y., Saeki, M., Sawada, J., Tohkin, M., Hasegawa, R. Racial variability in haplotype frequencies of UGT1A1 and glucuronidation activity of a novel single nucleotide polymorphism 686C-T (P229L) found in an African-American. Drug. Metab. Dispos. 33: 458-465, 2005. [PubMed: 15572581] [Full Text: https://doi.org/10.1124/dmd.104.001800]
Kaplan, M., Hammerman, C., Renbaum, P., Klein, G., Levy-Lahad, E. Gilbert's syndrome and hyperbilirubinaemia in ABO-incompatible neonates. Lancet 356: 652-653, 2000. [PubMed: 10968441] [Full Text: https://doi.org/10.1016/S0140-6736(00)02610-6]
Kaplan, M., Renbaum, P., Levy-Lahad, E., Hammerman, C., Lahad, A., Beutler, E. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc. Nat. Acad. Sci. 94: 12128-12132, 1997. [PubMed: 9342374] [Full Text: https://doi.org/10.1073/pnas.94.22.12128]
Kimura, T., Akaba, K., Ikegami, T., Akiba, K., Kanazawa, C., Katsuura, M., Shimizu, Y., Imaizumi, M., Lin, C., Hayasaka, K. Intermittent jaundice in patients with acute leukaemia: a common mutation of the bilirubin uridine-diphosphate glucuronosyltransferase gene among Asians. J. Inherit. Metab. Dis. 22: 747-753, 1999. [PubMed: 10472535] [Full Text: https://doi.org/10.1023/a:1005552302264]
King, C. D., Rios, G. R., Tephly, T. R. UDP-glucuronosyltransferases. Curr. Drug Metab. 1: 143-161, 2000. [PubMed: 11465080] [Full Text: https://doi.org/10.2174/1389200003339171]
Koiwai, O., Nishizawa, M., Hasada, K., Aono, S., Adachi, Y., Mamiya, N., Sato, H. Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum. Molec. Genet. 4: 1183-1186, 1995. [PubMed: 8528206] [Full Text: https://doi.org/10.1093/hmg/4.7.1183]
Kren, B. T., Parashar, B., Bandyopadhyay, P., Chowdhury, N. R., Chowdhury, J. R., Steer, C. J. Correction of the UDP-glucuronosyltransferase gene defect in the Gunn rat model of Crigler-Najjar syndrome type I with a chimeric oligonucleotide. Proc. Nat. Acad. Sci. 96: 10349-10354, 1999. [PubMed: 10468611] [Full Text: https://doi.org/10.1073/pnas.96.18.10349]
Labrune, P., Myara, A., Chalas, J., Le Bihan, B., Capel, L., Francoual, J. Association of a homozygous (TA)8 promoter polymorphism and a N400D mutation of UGT1A1 in a child with Crigler-Najjar type II syndrome. (Letter) Hum. Mutat. 20: 399-401, 2002. [PubMed: 12402338] [Full Text: https://doi.org/10.1002/humu.10122]
Lee, J. S., Wang, J., Martin, M., Germer, S., Kenwright, A., Benayed, R., Spleiss, O., Platt, A., Pilson, R., Hemmings, A., Weinblatt, M. E., Kaplowitz, N., Krasnow, J. Genetic variation in UGT1A1 typical of Gilbert syndrome is associated with unconjugated hyperbilirubinemia in patients receiving tocilizumab. Pharmacogenet. Genomics 21: 365-374, 2011. [PubMed: 21412181] [Full Text: https://doi.org/10.1097/FPC.0b013e32834592fe]
Lin, J.-P., Cupples, L. A., Wilson, P. W. F., Heard-Costa, N., O'Donnell, C. J. Evidence for a gene influencing serum bilirubin on chromosome 2q telomere: a genomewide scan in the Framingham Study. Am. J. Hum. Genet. 72: 1029-1034, 2003. [PubMed: 12618960] [Full Text: https://doi.org/10.1086/373964]
Lin, R., Wang, X., Wang, Y., Zhang, F., Wang, Y., Fu, W., Yu, T., Li, S., Xiong, M., Huang, W., Jin, L. Association of polymorphisms in four bilirubin metabolism genes with serum bilirubin in three Asian populations. Hum. Mutat. 30: 609-615, 2009. [PubMed: 19243019] [Full Text: https://doi.org/10.1002/humu.20895]
Mackenzie, P. I., Bock, K. W., Burchell, B., Guillemette, C., Ikushiro, S., Iyanagi, T., Miners, J. O., Owens, I. S., Nebert, D. W. Nomenclature update for the mammalian UDP glycosyltransferase (UGT) gene superfamily. Pharmacogenet. Genomics 15: 677-685, 2005. [PubMed: 16141793] [Full Text: https://doi.org/10.1097/01.fpc.0000173483.13689.56]
Mackenzie, P. I., Owens, I. S., Burchell, B., Bock, K. W., Bairoch, A., Belanger, A., Fournel-Gigleux, S., Green, M., Hum, D. W., Iyanagi, T., Lancet, D., Louisot, P., Magalou, J., Roy Chowdhury, J., Ritter, J. K., Schachter, H., Tephly, T. R., Tipton, K. E., Nebert, D. W. The UDP glycosyltransferase gene superfamily: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 7: 255-269, 1997. [PubMed: 9295054] [Full Text: https://doi.org/10.1097/00008571-199708000-00001]
Mackenzie, P. I. The cDNA sequence and expression of a variant 17-beta-hydroxysteroid UDP-glucuronosyltransferase. J. Biol. Chem. 265: 8699-8703, 1990. [PubMed: 1692835]
Maruo, Y., D'Addario, C., Mori, A., Iwai, M., Takahashi, H., Sato, H., Takeuchi, Y. Two linked polymorphic mutations (A(TA)7TAA and T-3279G) of UGT1A1 as the principal cause of Gilbert syndrome. Hum. Genet. 115: 525-526, 2004. [PubMed: 15378351] [Full Text: https://doi.org/10.1007/s00439-004-1183-x]
Maruo, Y., Nishizawa, K., Sato, H., Sawa, H., Shimada, M. Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene. Pediatrics 106: e59, 2000. Note: Electronic Article. [PubMed: 11061796] [Full Text: https://doi.org/10.1542/peds.106.5.e59]
Maruo, Y., Poon, K. K.-H., Ito, M., Iwai, M., Takahashi, H., Mori, A., Sato, H., Takeuchi, Y. Co-occurrence of three different mutations in the bilirubin UDP-glucuronosyltransferase gene in a Chinese family with Crigler-Najjar syndrome type I and Gilbert's syndrome. Clin. Genet. 64: 420-423, 2003. [PubMed: 14616765] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00136.x]
Maruo, Y., Wada, S., Yamamoto, K., Sato, H., Yamano, T., Shimada, M. A case of anorexia nervosa with hyperbilirubinaemia in a patient homozygous for a mutation in the bilirubin UDP-glucuronosyltransferase gene. Europ. J. Pediat. 158: 547-549, 1999. [PubMed: 10412811] [Full Text: https://doi.org/10.1007/s004310051143]
Miles, J. S., Moss, J. E., Taylor, B. A., Burchell, B., Wolf, C. R. Mapping genes encoding drug-metabolizing enzymes in recombinant inbred mice. Genomics 11: 309-316, 1991. [PubMed: 1685137] [Full Text: https://doi.org/10.1016/0888-7543(91)90137-4]
Moghrabi, N., Clarke, D. J., Boxer, M., Burchell, B. Identification of an A-to-G missense mutation in exon 2 of the UGT1 gene complex that causes Crigler-Najjar syndrome type 2. Genomics 18: 171-173, 1993. [PubMed: 8276413] [Full Text: https://doi.org/10.1006/geno.1993.1451]
Moghrabi, N., Clarke, D. J., Burchell, B., Boxer, M. Cosegregation of intragenic markers with a novel mutation that causes Crigler-Najjar syndrome type I: implication in carrier detection and prenatal diagnosis. Am. J. Hum. Genet. 53: 722-729, 1993. [PubMed: 8102509]
Moghrabi, N., Sutherland, L., Wooster, R., Povey, S., Boxer, M., Burchell, B. Chromosomal assignment of human phenol and bilirubin UDP-glucuronosyltransferase genes (UGT1A-subfamily). Ann. Hum. Genet. 56: 81-91, 1992. [PubMed: 1503396] [Full Text: https://doi.org/10.1111/j.1469-1809.1992.tb01134.x]
Monaghan, G., McLellan, A., McGeeban, A., Li Volti, S., Mollica, F., Salemi, I., Din, Z., Cassidy, A., Hume, R., Burchell, B. Gilbert's syndrome is a contributory factor in prolonged unconjugated hyperbilirubinemia of the newborn. J. Pediat. 134: 441-446, 1999. [PubMed: 10190918] [Full Text: https://doi.org/10.1016/s0022-3476(99)70201-5]
Nagai, F., Homma, H., Tanase, H., Matsui, M. Studies on the genetic linkage of bilirubin and androsterone UDP-glucuronyltransferases by cross-breeding of two mutant rat strains. Biochem. J. 252: 897-900, 1988. Note: Erratum: Biochem. J. 255: following 1061 only, 1988. [PubMed: 3138978] [Full Text: https://doi.org/10.1042/bj2520897]
Nguyen, N., Bonzo, J. A., Chen, S., Chouinard, S., Kelner, M. J., Hardiman, G., Belanger, A., Tukey, R. H. Disruption of the Ugt1 locus in mice resembles human Crigler-Najjar type I disease. J. Biol. Chem. 283: 7901-7911, 2008. [PubMed: 18180294] [Full Text: https://doi.org/10.1074/jbc.M709244200]
Ohnishi, A., Emi, Y. Rapid proteasomal degradation of translocation-deficient UDP-glucuronosyltransferase 1A1 proteins in patients with Crigler-Najjar type II. Biochem. Biophys. Res. Commun. 310: 735-741, 2003. [PubMed: 14550264] [Full Text: https://doi.org/10.1016/j.bbrc.2003.09.072]
Peters, W. H. M., Jansen, P. L. M., Nauta, H. The molecular weights of UDP-glucuronyltransferase determined with radiation-inactivation analysis: a molecular model of bilirubin UDP-glucuronyltransferase. J. Biol. Chem. 259: 11701-11705, 1984. [PubMed: 6480579]
Petit, F., Gajdos, V., Capel, L., Parisot, F., Myara, A., Francoual, J., Labrune, P. Crigler-Najjar type II syndrome may result from several types and combinations of mutations in the UGT1A1 gene. (Letter) Clin. Genet. 69: 525-527, 2006. [PubMed: 16712705] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00616.x]
Petit, F. M., Gajdos, V., Parisot, F., Capel, L., Aboura, A., Lachaux, A., Tachdjian, G., Pous, C., Labrune, P. Paternal isodisomy for chromosome 2 as the cause of Crigler-Najjar type I syndrome. Europ. J. Hum. Genet. 13: 278-282, 2005. [PubMed: 15586176] [Full Text: https://doi.org/10.1038/sj.ejhg.5201342]
Premawardhena, A., Fisher, C. A., Fathiu, F., de Silva, S., Perera, W., Peto, T. E. A., Olivieri, N. F., Weatherall, D. J. Genetic determinants of jaundice and gallstones in haemoglobin E beta-thalassemia. Lancet 357: 1945-1946, 2001. [PubMed: 11425418] [Full Text: https://doi.org/10.1016/s0140-6736(00)05082-0]
Premawardhena, A., Fisher, C. A., Liu, Y. T., Verma, I. C., de Silva, S., Arambepola, M., Clegg, J. B., Weatherall, D. J. The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications. Blood Cells Molec. Dis. 31: 98-101, 2003. [PubMed: 12850492] [Full Text: https://doi.org/10.1016/s1079-9796(03)00071-8]
Ritter, J. K., Chen, F., Sheen, Y. Y., Tran, H. M., Kimura, S., Yeatman, M. T., Owens, I. S. A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini. J. Biol. Chem. 267: 3257-3261, 1992. [PubMed: 1339448]
Ritter, J. K., Crawford, J. M., Owens, I. S. Cloning of two human liver bilirubin UDP-glucuronosyltransferase cDNAs with expression in COS-1 cells. J. Biol. Chem. 266: 1043-1047, 1991. [PubMed: 1898728]
Ritter, J. K., Yeatman, M. T., Ferreira, P., Owens, I. S. Identification of a genetic alteration in the code for bilirubin UDP-glucuronosyltransferase in the UGT1 gene complex of a Crigler-Najjar type I patient. J. Clin. Invest. 90: 150-155, 1992. [PubMed: 1634606] [Full Text: https://doi.org/10.1172/JCI115829]
Ritter, J. K., Yeatman, M. T., Kaiser, C., Gridelli, B., Owens, I. S. A phenylalanine codon deletion at the UGT1 gene complex locus of a Crigler-Najjar type I patient generates a pH-sensitive bilirubin UDP-glucuronosyltransferase. J. Biol. Chem. 268: 23573-23579, 1993. [PubMed: 8226884]
Rosatelli, M. C., Meloni, A., Faa, V., Saba, L., Crisponi, G., Clemente, M. G., Meloni, G., Piga, M. T., Cao, A. Molecular analysis of patients of Sardinian descent with Crigler-Najjar syndrome type I. J. Med. Genet. 34: 122-125, 1997. [PubMed: 9039987] [Full Text: https://doi.org/10.1136/jmg.34.2.122]
Roses, A. D. Pharmacogenetics and drug development: the path to safer and more effective drugs. Nature Rev. Genet. 5: 645-656, 2004. [PubMed: 15372086] [Full Text: https://doi.org/10.1038/nrg1432]
Sampietro, M., Lupica, L., Perrero, L., Comino, A., Martinez di Montemuros, F., Cappellini, M. D., Fiorelli, G. The expression of uridine diphosphate glucuronosyltransferase gene is a major determinant of bilirubin level in heterozygous beta-thalassaemia and in glucose-6-phosphate dehydrogenase deficiency. Brit. J. Haemat. 99: 437-439, 1997. [PubMed: 9375769] [Full Text: https://doi.org/10.1046/j.1365-2141.1997.4113228.x]
Sato, H., Sakai, Y., Koiwai, O., Watanabe, T. Mapping of the mouse bilirubin UDP-glucuronosyltransferase gene (Gnt-1) to chromosome 1 by restriction fragment length variations. Biochem. Genet. 30: 347-352, 1992. [PubMed: 1359870] [Full Text: https://doi.org/10.1007/BF00569325]
Sato, H., Uchida, T., Toyota, K., Kanno, M., Hashimoto, T., Watanabe, M., Nakamura, T., Tamiya, G., Aoki, K., Hayasaka, K. Association of breast-fed neonatal hyperbilirubinemia with UGT1A1 polymorphisms: 211G-A (G71R) mutation becomes a risk factor under inadequate feeding. J. Hum. Genet. 58: 7-10, 2013. [PubMed: 23014115] [Full Text: https://doi.org/10.1038/jhg.2012.116]
Seppen, J., Bosma, P. J., Goldhoorn, B. G., Bakker, C. T. M., Chowdhury, J. R., Chowdhury, N. R., Jansen, P. L. M., Oude Elferink, R. P. J. Discrimination between Crigler-Najjar type I and II by expression of mutant bilirubin uridine diphosphate-glucuronosyltransferase. J. Clin. Invest. 94: 2385-2391, 1994. [PubMed: 7989595] [Full Text: https://doi.org/10.1172/JCI117604]
Seppen, J., Steenken, E., Lindhout, D., Bosma, P. J., Oude Elferink, R. P. J. A mutation which disrupts the hydrophobic core of the signal peptide of bilirubin UDP-glucuronosyltransferase, an endoplasmic reticulum membrane protein, causes Crigler-Najjar type II. FEBS Lett. 390: 294-298, 1996. [PubMed: 8706880] [Full Text: https://doi.org/10.1016/0014-5793(96)00677-1]
Strassburg, C. P., Oldhafer, K., Manns, M. P., Tukey, R. H. Differential expression of the UGT1A locus in human liver, biliary, and gastric tissue: identification of UGT1A7 and UGT1A10 transcripts in extrahepatic tissue. Molec. Pharm. 52: 212-220, 1997. [PubMed: 9271343] [Full Text: https://doi.org/10.1124/mol.52.2.212]
Strassburg, C. P. Pharmacogenetics of Gilbert's syndrome. Pharmacogenomics 9: 703-715, 2008. [PubMed: 18518849] [Full Text: https://doi.org/10.2217/14622416.9.6.703]
Sugatani, J., Yamakawa, K., Yoshinari, K., Machida, T., Takagi, H., Mori, M., Kakizaki, S., Sueyoshi, T., Negishi, M., Miwa, M. Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. Biochem. Biophys. Res. Commun. 292: 492-497, 2002. [PubMed: 11906189] [Full Text: https://doi.org/10.1006/bbrc.2002.6683]
Suhre, K., Shin, S.-Y., Petersen, A.-K., Mohney, R. P., Meredith, D., Wagele, B., Altmaier, E., CARDIoGRAM, Deloukas, P., Erdmann, J., Grundberg, E., Hammond, C. J., and 22 others. Human metabolic individuality in biomedical and pharmaceutical research. Nature 477: 54-60, 2011. [PubMed: 21886157] [Full Text: https://doi.org/10.1038/nature10354]
Tukey, R. H., Strassburg, C. P. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu. Rev. Pharmacol. Toxicol. 40: 581-616, 2000. [PubMed: 10836148] [Full Text: https://doi.org/10.1146/annurev.pharmtox.40.1.581]
Udomuksorn, W., Elliot, D. J., Lewis, B. C., Mackenzie, P. I., Yoovathaworn, K., Miners, J. O. Influence of mutations associated with Gilbert and Crigler-Najjar type II syndromes on the glucuronidation kinetics of bilirubin and other UDP-glucuronosyltransferase 1A substrates. Pharmacogenet. Genomics 17: 1017-1029, 2007. [PubMed: 18004206] [Full Text: https://doi.org/10.1097/FPC.0b013e328256b1b6]
Ueyama, H., Koiwai, O., Soeda, Y., Sato, H., Satoh, Y., Ohkubo, I., Doida, Y. Analysis of the promoter of human bilirubin UDP-glucuronosyltransferase gene (UGT1*1) in relevance to Gilbert's syndrome. Hepatol. Res. 9: 152-163, 1997.
van Es, H. H., Bout, A., Liu, J., Anderson, L., Duncan, A. M., Bosma, P., Oude Elferink, R., Jansen, P. L., Roy Chowdhury, J., Schurr, E. Assignment of the human UDP glucuronosyltransferase gene (UGT1A1) to chromosome region 2q37. Cytogenet. Cell Genet. 63: 114-116, 1993. [PubMed: 8467709] [Full Text: https://doi.org/10.1159/000133513]
Wooster, R., Sutherland, L., Ebner, T., Clarke, D., Da Cruz e Silva, O., Burchell, B. Cloning and stable expression of a new member of the human liver phenol/bilirubin:UDP-glucuronosyltransferase cDNA family. Biochem. J. 278: 465-469, 1991. [PubMed: 1910331] [Full Text: https://doi.org/10.1042/bj2780465]
Yamamoto, K., Soeda, Y., Kamisako, T., Hosaka, H., Fukano, M., Sato, H., Fujiyama, Y., Adachi, Y., Satoh, Y., Bamba, T. Analysis of bilirubin uridine 5-prime-diphosphate (UDP)-glucuronosyltransferase gene mutations in seven patients with Crigler-Najjar syndrome type II. J. Hum. Genet. 43: 111-114, 1998. [PubMed: 9621515] [Full Text: https://doi.org/10.1007/s100380050050]
Zahreddine, H. A., Culjkovic-Kraljacic, B., Assouline, S., Gendron, P., Romeo, A. A., Morris, S. J., Cormack, G., Jaquith, J. B., Cerchietti, L., Cocolakis, E., Amri, A., Bergeron, J., Leber, B., Becker, M. W., Pei, S., Jordan, C. T., Miller, W. H., Jr., Borden, K. L. B. The sonic hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature 511: 90-93, 2014. [PubMed: 24870236] [Full Text: https://doi.org/10.1038/nature13283]