Identification of single nucleotide polymorphisms in the multidrug resistance‐associated protein 4 (MRP4)

The multidrug resistance‐associated protein 4 (MRP4, ABCC4) is an ATP‐binding cassette efflux transporter involved in the transport of nucleoside analogues. Genetic heterogeneity in MRP4 could influence the expression or intrinsic activity of this transporter and consequently alter the disposition profile or the efficacy of certain antiviral agents. In order to identify single nucleotide polymorphisms (SNPs), PCR was performed on genomic DNA samples from 96 Caucasians and analyzed by direct sequencing. In order to maximize the likelihood of identifying SNPs most likely to result in loss of transporter function, six exonic regions in MRP4 encompassing the key membrane spanning domain (MSD) or the nucleotide‐binding domains (NBD) were assessed. (See Table) Three non‐synonymous SNPs were identified. Two of these SNPs, G912T and G2269A, predict major amino acid changes within MSD1 and MSD2, respectively. No SNPs were identified in exons 12 and 19. The functional relevance of MRP4 variants is currently being evaluated using OAT‐1/MRP4 double transfected HeLa cells. Clinical Pharmacology & Therapeutics (2004) 75 , P93–P93; doi: 10.1016/j.clpt.2003.11.354MRP4 variant Amino acid change xon Domain Mutant allele frequency (%)G912T K304N MSD1 9.4 G951A synonymous MSD1 37 G969A synonymous MSD1 35.9 G1035A * synonymous 8 MSD1 1 G1141A * synonymous 8 MSD1 0.5 A2230G * M7744V 3 MSD2 0.5 G2269A E757K 8 MSD2 1.6 G2844T synonymous NBD2 5.9 G3609A * synonymous1.6* novel SNPs