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Originally published in Science Express on 21 December 2006
Science 26 January 2007:
Vol. 315. no. 5811, pp. 525 - 528
DOI: 10.1126/science.1135308
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Reports

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

Chava Kimchi-Sarfaty,*{dagger} Jung Mi Oh,{dagger}{ddagger} In-Wha Kim, Zuben E. Sauna, Anna Maria Calcagno, Suresh V. Ambudkar, Michael M. Gottesman{dagger}

Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. 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 and protein levels, 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 cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.

* Present address: Center for Biologics Evaluation and Research, Food and Drug Administration, 29 Lincoln Drive, Room 316, Bethesda, MD 20892, USA.

{ddagger} Present address: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.

{dagger} To whom correspondence should be addressed. E-mail: mgottesman{at}nih.gov (M.M.G.); jmoh{at}snu.ac.kr (J.M.O.); kimchi{at}cber.fda.gov (C.K.-S.)

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