Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: Correlation of genotype to phenotype

Abstract

Uridine‐diphosphoglucuronate glucuronosyltransferases (UGTs) are a family of enzymes that conjugate various endogenous and exogenous compounds with glucuronic acid and facilitate their excretion in the bile. Bilirubin‐UGT1 (UGT1A1) is the only isoform that significantly contributes to the conjugation of bilirubin. Lesions in the gene encoding bilirubin‐UGT1, lead to complete or partial inactivation of the enzyme causing the rare autosomal recessively inherited conditions, Crigler‐Najjar syndrome type‐1 (CN‐1) and type 2 (CN‐2), respectively. Inactivation of the enzyme leads to accumulation of unconjugated bilirubin in the serum. Severe hyperbilirubinemia seen in CN‐1 can cause bilirubin encephalopathy (kernicterus). Kernicterus can be fatal or may leave behind permanent neurological sequelae. Here, we have compiled more than 50 genetic lesions of UGT1A1 that cause CN‐1 (including 9 novel mutations) or CN‐2 (including 3 novel mutations) and have presented a correlation of structure to function of UGT1A1. In contrast to Crigler‐Najjar syndromes, Gilbert syndrome is a common inherited condition characterized by mild hyperbilirubinemia. An insertional mutation of the TATAA element upstream to UGT1A1 results in a reduced level of expression of the gene. Homozygosity for the variant promoter is required for Gilbert syndrome, but not sufficient for manifestation of hyperbilirubinemia, which is partly dependent on the rate of bilirubin production. Several structural mutations of UGT1A1, for example, a G71R substitution, have been reported to cause mild reduction of UGT activity toward bilirubin, resulting in mild hyperbilirubinemia, 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, consistent with the diagnosis of CN‐2, may be observed. Hum Mutat 16:297–306, 2000. © 2000 Wiley‐Liss, Inc.

Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects

“…It has been shown that homozygous or compound heterozygous mutations of the UGT1A1 gene can lead to these inheritable unconjugated hyperbilirubinemias, and over 30 variants have been identified. 15,16 The promoter region and exon 1 of the UGT1A1 gene contain the most common phenotype-associated polymorphisms: an insertion/deletion of TA 6 /TA 7 (UGT1A1*28) and a nonsynonymous coding variant 211G4A (G71R, UGT1A1*6), respectively. The UGT1A1*28 allele is common in Caucasian populations and in those of African origin (0.26-0.56) 17 and defines the genetic basis of Gilbert syndrome.…”

“…The minimum P-value was 8.12Â10 16 at rs4148325, explaining about 7.9% of the variance in log-transformed serum total bilirubin levels. The proportion of variance explained by the remaining two SNPs was about 5.3% at rs4148323 (4.5% by additive effect and 0.8% by dominance deviation) and 0.9% at rs4148326.…”

UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer

“…Although more than 50 genetic lesions in the UGT1A1 gene have been described (Kadakol et al, 2000), the UGT1A1*28 allele (the most frequent polymorphism in Caucasian populations) plays a crucial role in the development of toxicity after irinotecan chemotherapy. Symbols of (6/6), (6/7) and (7/7) denote homozygous absence of the variant allele, heterozygous, and homozygous for the variant allele, respectively.…”

“…The UGT1A1 gene consists of at least nine promoters and first exons (first exons 3, 11 and 12 are pseudogenes) that can be spliced with four common exons to result in nine different UGT1A1 enzymes (Ritter et al, 1992;Owens and Ritter, 1995). More than 50 genetic variations in the promoter and coding regions of the gene are currently known to decrease the enzyme activity (Kadakol et al, 2000), leading to constitutional unconjugated jaundice (Crigler-Najjar or Gilbert's syndromes). One of the most common genotypes causing Gilbert's syndrome in Caucasian populations is the inheritance of a promoter region containing an extra TA dinucleotide [A(TA) 7 TAA], which results in a 70% reduction in transcriptional activity compared with wild-type UGT1A1 [A(TA) 6 TAA].…”

Comparative genomics analysis of human sequence variation in the UGT1A gene cluster

“…Diminished production or activity of this enzyme leads to the hyperbilirubinemic syndromes described by CriglerNajjar and Gilbert [5][6][7][8] ; these syndromes have been associated with several common and rare variants of UGT1A1. 1, [8][9][10][11] Genome-wide scanning of healthy human pedigrees has linked serum bilirubin levels most strongly to the chromosome 2q37 region containing UGT1A. 12 However, bilirubin levels also depend on the rate of production of bilirubin.…”