Correcting the cystic fibrosis disease mutant, A455E CFTR

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Abstract

Cystic fibrosis is caused by more than 1000 mutations, the most common being the ΔF508 mutation. These mutations have been divided into five classes [1], with ΔF508 CFTR in class II. Here we have studied the class V mutation A455E. We report that the mature and immature bands of A455E are rapidly degraded primarily by proteasomes; the short protein half-life of this mutant therefore resembles that of ΔF508 CFTR. A455E could be rescued by treatment of the cells with proteasome inhibitors. Furthermore, co-transfection of A455E with the truncation mutant Δ264 CFTR also rescued the mature C band, indicating that A455E can be rescued by transcomplementation. We found that Δ264 CFTR bound to A455E, forming a bimolecular complex. Treatment with the compound correctors C3 and C4 also rescued A455E. These results are significant because they show that although ΔF508 belongs to a different class than A455E, it can be rescued by the same strategies, offering therapeutic promise to patients with Class V mutations. © 2014 Cebotaru et al.

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Cebotaru, L., Rapino, D., Cebotaru, V., & Guggino, W. B. (2014). Correcting the cystic fibrosis disease mutant, A455E CFTR. PLoS ONE, 9(1). https://doi.org/10.1371/journal.pone.0085183

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