Abstract
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 characterized. Our aims were to describe the clinical and molecular phenotypes associated with R751L. Relevant clinical data were collected from three heterozygote individuals harboring 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 with 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, was not different from wild-type CFTR. Overall, R751L-CFTR was associated with reduced sodium chloride absorption but had functional properties similar to wild-type CFTR. This is the first report of R751L-CFTR that combines clinical phenotype with characterization 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.
Highlights
Cystic fibrosis (CF) is a life-limiting autosomal recessive condition arising from mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein [1]
The combined actions of R domain phosphorylation, ATP binding to the NBDs, and subsequent transmembrane domain (TMD) conformational change result in CFTR activation and chloride secretion [8]
F508del/ F508del human bronchial epithelial cultures (HBEs) responses to forskolin and CFTRinh-172 were significantly lower than those seen with non-CF HBEs due to the lack of functional CFTR (P < 0.05). These findings demonstrate residual CFTR function in F508del/R751L HBEs, which was smaller in magnitude than in non-CF HBEs
Summary
Cystic fibrosis (CF) is a life-limiting autosomal recessive condition arising from mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein [1]. This gives rise to multisystem disease involving chronic respiratory infection and inflammation, pancreatic exocrine insufficiency, and complications of CF, including CF-related diabetes, liver disease, and male infertility [2]. Defective chloride and bicarbonate transport by CFTR leads to airway surface dehydration and acidification [3,4,5] This results in impaired mucociliary clearance, chronic endobronchial infection, neutrophilic inflammation, and eventual respiratory failure [2, 6]. The combined actions of R domain phosphorylation, ATP binding to the NBDs, and subsequent TMD conformational change result in CFTR activation and chloride secretion [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: American Journal of Physiology-Lung Cellular and Molecular Physiology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
