Laselva Onofrio, Ardelean Maria C, Bear Christine E
Programme in Molecular Medicine, Hospital for Sick Children, Toronto, ON M5G 8X4, Canada.
Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy.
J Pers Med. 2021 Apr 15;11(4):301. doi: 10.3390/jpm11040301.
The rare Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, c.1826A > G (H609R) and c.3067_3072delATAGTG (I1023_V1024del), are associated with severe lung disease. Despite the existence of four CFTR targeted therapies, none have been approved for individuals with these mutations because the associated molecular defects were not known. In this study we examined the consequences of these mutations on protein processing and channel function in HEK293 cells. We found that, similar to F508del, H609R and I1023_V1024del-CFTR exhibited reduced protein processing and altered channel function. Because the I1023_V1024del mutation can be linked with the mutation, I148T, we also examined the protein conferred by transfection of a plasmid bearing both mutations. Interestingly, together with I148T, there was no further reduction in channel function exhibited by I1023-V1024del. Both H609R and I1023_V1024del failed to exhibit significant correction of their functional expression with lumacaftor and ivacaftor. In contrast, the triple modulator combination found in TRIKAFTA, i.e., tezacaftor, elexacaftor and ivacaftor rescued trafficking and function of both of these mutants. These in-vitro findings suggest that patients harbouring H609R or I1023_V1024del, alone or with I148T, may benefit clinically from treatment with TRIKAFTA.
罕见的囊性纤维化跨膜传导调节因子（CFTR）突变，即c.1826A > G（H609R）和c.3067_3072delATAGTG（I1023_V1024del），与严重的肺部疾病相关。尽管存在四种CFTR靶向疗法，但尚无一种被批准用于携带这些突变的个体，因为相关的分子缺陷尚不清楚。在本研究中，我们检测了这些突变对HEK293细胞中蛋白质加工和通道功能的影响。我们发现，与F508del相似，H609R和I1023_V1024del-CFTR表现出蛋白质加工减少和通道功能改变。由于I1023_V1024del突变可与I148T突变相关联，我们还检测了转染携带这两种突变的质粒所表达的蛋白质。有趣的是，与I148T一起，I1023-V1024del并未表现出通道功能的进一步降低。H609R和I1023_V1024del均未因鲁马卡托和依伐卡托而使其功能表达得到显著校正。相比之下，在TRIKAFTA中发现的三联调节剂组合，即替扎卡托、依列卡托和依伐卡托挽救了这两种突变体的转运和功能。这些体外研究结果表明，携带H609R或I1023_V1024del单独或与I148T一起的患者可能在临床上从TRIKAFTA治疗中获益。
