A "silent" polymorphism in the MDR1 gene changes substrate specificity - PubMed (original) (raw)

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

doi: 10.1126/science.1135308. Epub 2006 Dec 21.

Affiliations

• PMID: 17185560
• DOI: 10.1126/science.1135308

A "silent" polymorphism in the MDR1 gene changes substrate specificity

Chava Kimchi-Sarfaty et al. Science. 2007.

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.

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Comment in

• Genetics. SNPs, silent but not invisible.
  Komar AA. Komar AA. Science. 2007 Jan 26;315(5811):466-7. doi: 10.1126/science.1138239. Epub 2006 Dec 21. Science. 2007. PMID: 17185559 No abstract available.
• How do synonymous mutations affect fitness?
  Parmley JL, Hurst LD. Parmley JL, et al. Bioessays. 2007 Jun;29(6):515-9. doi: 10.1002/bies.20592. Bioessays. 2007. PMID: 17508390
• Drug resistance in epilepsy: more twists in the tale.
  Sisodiya SM, Goldstein DB. Sisodiya SM, et al. Epilepsia. 2007 Dec;48(12):2369-70. doi: 10.1111/j.1528-1167.2007.01260_1.x. Epilepsia. 2007. PMID: 18088268 No abstract available.

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