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    Science. 2007 Jan 26;315(5811):525-8. Epub 2006 Dec 21.

    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.

    Source

    Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. kimchi@cber.fda.gov

    Erratum in

    • Science. 2007 Nov 30;318(5855):1382-3.
    • Science. 2011 oCT 7;334(6052):39.

    Abstract

    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.

    Comment in

    PMID:
    17185560
    [PubMed - indexed for MEDLINE]

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