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.