Scientific Publications by FDA Staff

Science 2007 Jan 26;315(5811):525-8

A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity.

Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM

Gottesman MM (reprint author), US FDA, Ctr Biol Evaluat & Res, 29 Lincoln Dr,Room 316, Bethesda, MD 20892 USA NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA

Synonymous Single Nucleotide Polymorphisms (SNPs) do not change the coding sequences, and, therefore, are not expected to change the function of the protein in which they occur. Here, we report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product, P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA levels and protein, but altered conformations were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of co-translational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.