ClinVar

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.