Revisiting the effects of MDR1 Variants using computational approaches

Abstract

AbstractP-glycoprotein, encoded by the MDR1 gene, is an ATP-dependent pump that exports various substances out of cells. Its overexpression is related to multi drug resistance in many cancers. Numerous studies explored the effects of MDR1 variants on p-glycoprotein expression and function, and on patient survivability. T1236C, T2677C and T3435C are prevalent MDR1 variants that are the most widely studied, typically in-vitro and in-vivo, with remarkably inconsistent results. In this paper we perform computational, data-driven analyses to assess the effects of these variants using a different approach. We use knowledge of gene expression regulation to elucidate the variants’ mechanism of action. Results indicate that T1236C increases MDR1 levels by 2-fold and is correlated with worse patient prognosis. Additionally, examination of MDR1 folding strength suggests that T3435C potentially modifies co-translational folding. Furthermore, all three variants reside in potential translation bottlenecks and likely cause increased translation rates. These results support several hypotheses suggested by previous studies. To the best of our knowledge, this study is the first to apply a computational approach to examine the effects of MDR1 variants.