Genetic variations of the ABC transporter gene ABCC3 in a Japanese population

An ATP-binding cassette transporter, multidrug resistance-related protein 3 (MRP3), is encoded by the ABCC3 gene. The MRP3 protein is expressed in several tissues, and functions as an efflux transporter for conjugated as well as unconjugated substrates. In this study, the 31 ABCC3 exons and their flanking introns were comprehensively screened for genetic variations in 89 Japanese subjects. Forty-six genetic variations, including 21 novel ones, were found: 8 were located in the 5'-flanking region, 14 in the coding exons (8 synonymous and 6 nonsynonymous variations), and 24 in the introns. Of these 46 variations, five novel nonsynonymous variations, 2221C>T (Gln741Stop), 2395G>A (Val799Met), 2798_2799delAG (Gln933ArgfsX64), 3657C>A (Ser1219Arg), and 4217C>T (Thr1406Met), were found as heterozygous variations. The allele frequencies were 0.011 for Ser1219Arg and 0.006 for the other four variations. Gln741Stop induces a stop codon at codon 741. Gln933ArgfsX64 causes a frame-shift at codon 933, resulting in early termination at codon 997. Both variations result in loss of 6 transmembrane helices (from the 12th to 17th helices) in the C-terminus and all regions of nucleotide binding domain 2. Thus, both variant proteins are assumed to be inactive. These data provide fundamental and useful information for pharmacogenetic studies on MRP3-transported drugs in Japanese.