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

✍ Scribed by Kimchi-Sarfaty, C.; Oh, J. M.; Kim, I.-W.; Sauna, Z. E.; Calcagno, A. M.; Ambudkar, S. V.; Gottesman, M. M.

• Book ID: 121672062
• Publisher: American Association for the Advancement of Science
• Year: 2007
• Tongue: English
• Weight: 509 KB
• Volume: 315
• Category: Article
• ISSN: 0036-8075
• DOI: 10.1126/science.1135308

✦ Synopsis

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 (
MDR

1. gene, part of a haplotype previously linked to altered function of the
   MDR
   1 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.