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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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   Abstract »    Full Text »    PDF »
A new strategy for assessing selenoprotein function: siRNA knockdown/knock-in targeting the 3'-UTR.
M.-H. Yoo, X.-M. Xu, A. A. Turanov, B. A. Carlson, V. N. Gladyshev, and D. L. Hatfield (2007)
RNA 13, 921-929
   Abstract »    Full Text »    PDF »
Frequency and phenotypic implications of mitochondrial DNA mutations in human squamous cell cancers of the head and neck.
S. Zhou, S. Kachhap, W. Sun, G. Wu, A. Chuang, L. Poeta, L. Grumbine, S. K. Mithani, A. Chatterjee, W. Koch, et al. (2007)
PNAS 104, 7540-7545
   Abstract »    Full Text »    PDF »

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