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Background: Gilbert syndrome is caused by defects in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene. These mutations differ among different populations and many of them have been found to be genetic risk factors for the development of neonatal jaundice. Objectives: The objective was to determine the frequencies of the following mutations in the UGT1A1 gene: A(TA)₇TAA (the most common cause of Gilbert syndrome in Caucasians), G71R (more common in the Japanese and Taiwanese population), and G493R (described in a homozygous Malay woman with Crigler-Najjar syndrome type 2) in a group of Malaysian babies with hyperbilirubinemia and a group of normal controls. Methods: The GeneScan fragment analysis was used to detect the A(TA)₇TAA variant. Mutation screening of both G71R and G493R was performed using denaturing high performance liquid chromatography. Results: Fourteen out of fifty-five neonates with hyperbilirubinemia (25%) carried the A(TA)₇TAA mutation (10 heterozygous, 4 homozygous). Seven out of fifty controls (14%) carried this mutation (6 heterozygous, 1 homozygous). The allelic frequencies for hyperbilirubinemia and control patients were 16 and 8%, respectively (p = 0.20). Heterozygosity for the G71R mutation was almost equal among both groups (5.5% for hyperbilirubinemia patients and 6.0% for controls; p = 0.61). One subject (1.8%) in the hyperbilirubinemia group and none of the controls were heterozygous for the G493R mutation (p = 0.476). Conclusions: The A(TA)₇TAA seems more common than the G71R and G493R mutations in the Malaysian population.

ABSTRACT:The uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene encodes the enzyme responsible for bilirubin glucuronidation. To evaluate the contribution of UGT1A1 promoter mutations to neonatal jaundice, we determined the genotypes of c.-3279TϾG, c.-3156GϾA, and A(TA)7TAA in Malay infants with neonatal jaundice (patients) and in infants without neonatal jaundice (controls). In our population study, only c.-3279TϾG was associated with neonatal jaundice. The genotype distributions between both groups were significantly different (p ϭ 0.003): the frequency of homozygosity for c.-3279G was much higher in patients than those in controls. Allele frequency of c.-3279G was significantly higher in patients than those in controls (p ϭ 0.006). We then investigated changes in transcriptional activity because of c.-3279TϾG. Luciferase reporter assay in HepG2 cells demonstrated that transcriptional activity of the c.-3279G allele was significantly lower than that of the c.-3279T allele in both the absence and presence of bilirubin. Luciferase reporter assay in COS-7 cells elucidated that c.-3279TϾG modified the synergistic effects of the nuclear factors associated with transcriptional machinery. In conclusion, the c.-3279TϾG mutation in the UGT1A1 promoter is a genetic risk factor for neonatal jaundice. T he uridine diphospho (UDP)-glucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene encodes bilirubin UDPglucuronosyltransferase (UGT1A1), which is the enzyme responsible for bilirubin glucuronidation. A decrease in UGT1A1 activity leads to unconjugated hyperbilirubinemia. Inherited UGT1A1 deficiencies because of UGT1A1 mutations are classified into three forms based on clinical severity: Crigler-Najjar syndrome type 1 (CN-1, a severe form), Crigler-Najjar syndrome type 2 (CN-2, an intermediate form), and Gilbert's syndrome (GS, a mild form) (1,2). Such inherited UGT1A1 deficiencies may cause neonatal jaundice.A mutant TATA box with an additional TA insertion, A(TA)7TAA, was first found in patients with CN-1, CN-2, and GS (3-5). GS with homozygosity for A(TA)7TAA accelerates or prolongs neonatal jaundice (6). This mutation is frequently observed in whites and Africans (7). Another GScausing gene mutation, c.211GϾA, is frequent in the East Asian population (8). The c.211GϾA mutation causes an amino acid change, glycine to arginine at codon 71.Recently, polymorphic mutations, c.-3279TϾG and c.-3156GϾA, were identified in the UGT1A1 promoter region (9,10). The c.-3279TϾG mutation is located in the phenobarbital responsive enhancer module (gtPBREM), which is activated by a nuclear receptor, constitutive androstane receptor (CAR) (11). Sugatani et al. (9) showed using luciferase reporter assay that mutant gtPBREM with c.-3279TϾG decreases the transcriptional activity of the UGT1A1 promoter by 60%. The c.-3156GϾA mutation is located between the gtPBREM and TATA box. A haplotype analysis showed that there is a high extent of linkage disequilibrium between c.-3156GϾA and A(TA)7TAA (10,12). However, it is unknown ...