A "silent" polymorphism in the MDR1 gene changes substrate specificity by Kimchi-Sarfaty Chava, Oh Jung Mi, Kim In-Wha, Sauna Zuben E, Calcagno Anna Maria, Ambudkar Suresh V, Gottesman Michael M in Science (New York, N.Y.) (2007).

[PMID: 17185560] PubMed


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.

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