Cystic fibrosis (CF) arises from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in progressive and life-limiting respiratory disease. R751L is a rare CFTR mutation that is poorly characterised. Our aims were to describe the clinical and molecular phenotypes associated with R751L. Relevant clinical data were collected from three heterozygote individuals harbouring R751L (2 patients with G551D/R751L and 1 with F508del/R751L). Assessment of R751L-CFTR function was made in primary human bronchial epithelial cultures (HBEs) and Xenopus oocytes. Molecular properties of R751L-CFTR were investigated in the presence of known CFTR modulators. Although sweat chloride was elevated in all three patients, the clinical phenotype associated with R751L was mild. Chloride secretion in F508del/R751L HBEs was reduced compared to non-CF HBEs and associated with a reduction in sodium absorption by the epithelial sodium channel (ENaC). However, R751L-CFTR function in Xenopus oocytes together with folding and cell surface transport of R751L-CFTR were not different to wild-type CFTR. Overall, R751L-CFTR was associated with reduced sodium chloride absorption but had similar functional properties to wild-type CFTR. This is the first report of R751L-CFTR that combines clinical phenotype with characterisation of functional and biological properties of the mutant channel. Our work will build upon existing knowledge of mutations within this region of CFTR and importantly inform approaches for clinical management. Elevated sweat chloride and reduced chloride secretion in HBEs may be due to alternative non-CFTR factors, which require further investigation.

中文翻译：

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R751L-CFTR突变的临床和分子特征

囊性纤维化 (CF) 源于 CF 跨膜电导调节 (CFTR) 基因的突变，导致进行性和限制生命的呼吸系统疾病。R751L 是一种罕见的 CFTR 突变，其特征很差。我们的目的是描述与 R751L 相关的临床和分子表型。从三个携带 R751L 的杂合子个体（2 名 G551D/R751L 患者和 1 名 F508del/R751L 患者）收集相关临床数据。R751L-CFTR 功能的评估是在原代人支气管上皮培养物 (HBE) 和爪蟾卵母细胞中进行的。在存在已知 CFTR 调节剂的情况下研究了 R751L-CFTR 的分子特性。尽管所有三名患者的汗液氯化物均升高，但与 R751L 相关的临床表型是轻微的。与非 CF HBE 相比，F508del/R751L HBE 中的氯化物分泌减少，并且与上皮钠通道 (ENaC) 对钠的吸收减少有关。然而，R751L-CFTR 在非洲爪蟾卵母细胞中的功能以及 R751L-CFTR 的折叠和细胞表面转运与野生型 CFTR 没有区别。总体而言，R751L-CFTR 与氯化钠吸收减少有关，但与野生型 CFTR 具有相似的功能特性。这是 R751L-CFTR 的第一份报告，它将临床表型与突变通道的功能和生物学特性的表征相结合。我们的工作将建立在 CFTR 这一区域内现有的突变知识的基础上，并重要地为临床管理方法提供信息。HBE中汗液氯化物升高和氯化物分泌减少可能是由于替代的非CFTR因素，