Functional analysis of genetic variants in the human concentrative nucleoside transporter 3 (CNT3; SLC28A3).

摘要: The human concentrative nucleoside transporter, CNT3 (SLC28A3), plays an important role in mediating the cellular entry of a broad array physiological nucleosides and synthetic anticancer analog drugs. As first step toward understanding genetic basis for interindividual differences disposition response to antileukemic analogs, we examined functional diversity CNT3. In all, 56 variable sites exons flanking intronic region SLC28A3 were identified collection 270 DNA samples from US populations (80 African-Americans, 80 European-Americans, 60 Asian-Americans, 50 Mexican-Americans). Of 16 coding variants, 12 had not been previously reported. Also, 10 resulted amino-acid changes three these total allele frequencies ≥1%. Nucleotide (π) at nonsynonymous synonymous was estimated be 1.81 × 104 18.13 104, respectively, suggesting that is under negative selection. All constructed by site-directed mutagenesis expressed Xenopus laevis oocytes, transported purine pyrimidine model substrates, except c. 1099G>A (p. Gly367Arg). This rare variant alters evolutionarily conserved site putative substrate recognition domain presence additional glycine residues vicinity p. Gly367Arg are also paralogs suggest critical function transporter family. analysis characterization variants this does tolerate fitness.