Molecular dynamics simulation study on structural instability of CFTR mutants in Japanese CF patients and effects of CFTR correctors on them.

Abstract

Cystic fibrosis (CF) is a genetic disorder caused by abnormal function of CFTR. CFTR is expressed in the lumen lateral membrane of the transport epithelia of the whole body, such as the gastrointestinal and the respiratory epithelia, and plays a central role in the anion transport. CF is common in Caucasians but relatively rare in Asians. Deletion of phenylalanine at position 508 (ΔF508) is the most common CF-associated mutation and causes defects in CFTR trafficking to the plasma membrane (class II). The CFTR mutation profiles in Japanese are far different from those in Caucasians. Recently, some CFTR correctors rescuing the ΔF508-CFTR from the trafficking defect were developed for by Vertex. Inc. We have confirmed that the Vertex correctors for the ΔF508 mutant could also rescue Japanese CF-associated mutants, H1085R and L441P.