Cystic fibrosis (CF) is caused by mutations that compromise the expression and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Most people with CF harbor a common misfolded variant (ΔF508) that can be partially rescued by therapeutic “correctors” that restore its expression. Nevertheless, many other CF variants are insensitive to correctors. Using deep mutational scanning, we quantitatively compare the effects of two correctors on the plasma membrane expression of 129 CF variants. Though structural calculations suggest corrector binding provides similar stabilization to most variants, it’s those with intermediate expression and mutations near corrector binding pockets that exhibit the greatest response. Deviations in sensitivity appear to depend on the degree of variant destabilization and the timing of misassembly. Combining correctors appears to rescue more variants by doubling the binding energy and stabilizing distinct cotranslational folding transitions. These results provide an overview of rare CF variant expression and establish new tools for precision pharmacology.

囊性纤维化 (CF) 是由损害囊性纤维化跨膜电导调节因子 (CFTR) 氯离子通道的表达和/或功能的突变引起的。大多数患有 CF 的人都携带一种常见的错误折叠变异 (ΔF508)，可以通过恢复其表达的治疗“校正器”部分挽救该变异。然而，许多其他 CF 变体对校正器不敏感。使用深度突变扫描，我们定量比较了两种校正剂对 129 个 CF 变体质膜表达的影响。尽管结构计算表明校正子结合为大多数变体提供了类似的稳定性，但那些在校正子结合口袋附近具有中间表达和突变的突变表现出最大的反应。灵敏度的偏差似乎取决于变体不稳定的程度和错误组装的时间。组合校正器似乎可以通过加倍结合能并稳定不同的共平移折叠转变来拯救更多变体。这些结果提供了罕见 CF 变异表达的概述，并为精准药理学建立了新工具。