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Am J Physiol Lung Cell Mol Physiol
2021 Feb 01;3202:L288-L300. doi: 10.1152/ajplung.00137.2020.
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Clinical and molecular characterization of the R751L-CFTR mutation.
Haq IJ
,
Althaus M
,
Gardner AI
,
Yeoh HY
,
Joshi U
,
Saint-Criq V
,
Verdon B
,
Townshend J
,
O'Brien C
,
Ben-Hamida M
,
Thomas M
,
Bourke S
,
van der Sluijs P
,
Braakman I
,
Ward C
,
Gray MA
,
Brodlie M
.
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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.
203520/Z/16/Z Wellcome Trust (Wellcome), MR/M008797/1 Medical Research Council (MRC), SRC003 and SRC013 Cystic Fibrosis Trust, ZonMw TOP 40-00812-98-14103 Netherlands Organisation for Health Research and Development (ZonMw), LIFT 731.017.404 Dutch Research Council, BRAAKM14XX0 Cystic Fibrosis Foundation (CFF), MR/M008797/1 Medical Research Council , Wellcome Trust
Azad,
Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease.
2009, Pubmed,
Xenbase
Azad,
Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease.
2009,
Pubmed
,
Xenbase
Boiko,
Pseudohypoaldosteronism type 1 and Liddle's syndrome mutations that affect the single-channel properties of the epithelial Na+ channel.
2015,
Pubmed
Bompadre,
CFTR gating I: Characterization of the ATP-dependent gating of a phosphorylation-independent CFTR channel (DeltaR-CFTR).
2005,
Pubmed
Bozoky,
Regulatory R region of the CFTR chloride channel is a dynamic integrator of phospho-dependent intra- and intermolecular interactions.
2013,
Pubmed
Brodlie,
Targeted therapies to improve CFTR function in cystic fibrosis.
2015,
Pubmed
Button,
A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia.
2012,
Pubmed
Clancy,
CFTR modulator theratyping: Current status, gaps and future directions.
2019,
Pubmed
Collaco,
Sources of Variation in Sweat Chloride Measurements in Cystic Fibrosis.
2016,
Pubmed
Cui,
Domain interdependence in the biosynthetic assembly of CFTR.
2007,
Pubmed
Durmowicz,
Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience.
2013,
Pubmed
Edelheit,
Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism.
2005,
Pubmed
Elborn,
Cystic fibrosis.
2016,
Pubmed
Fajac,
Combination of ENaC and CFTR mutations may predispose to cystic fibrosis-like disease.
2009,
Pubmed
Goubau,
Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis.
2009,
Pubmed
Gray,
Two types of chloride channel on duct cells cultured from human fetal pancreas.
1989,
Pubmed
Haq,
Airway surface liquid homeostasis in cystic fibrosis: pathophysiology and therapeutic targets.
2016,
Pubmed
Hoelen,
The primary folding defect and rescue of ΔF508 CFTR emerge during translation of the mutant domain.
2010,
Pubmed
Hwang,
Structural mechanisms of CFTR function and dysfunction.
2018,
Pubmed
Hwang,
Gating of the CFTR Cl- channel by ATP-driven nucleotide-binding domain dimerisation.
2009,
Pubmed
Kirchner,
Alteration of protein function by a silent polymorphism linked to tRNA abundance.
2017,
Pubmed
Kleizen,
Folding of CFTR is predominantly cotranslational.
2005,
Pubmed
Liu,
Molecular Structure of the Human CFTR Ion Channel.
2017,
Pubmed
,
Xenbase
Martin,
Ion channels as targets to treat cystic fibrosis lung disease.
2018,
Pubmed
McCaul,
Analysis of Protein Folding, Transport, and Degradation in Living Cells by Radioactive Pulse Chase.
2019,
Pubmed
Melis,
Revisiting CFTR inhibition: a comparative study of CFTRinh -172 and GlyH-101 inhibitors.
2014,
Pubmed
Mora-Lopez,
Novel mutation in the epithelial sodium channel causing type I pseudohypoaldosteronism in a patient misdiagnosed with cystic fibrosis.
2012,
Pubmed
Ostedgaard,
CFTR with a partially deleted R domain corrects the cystic fibrosis chloride transport defect in human airway epithelia in vitro and in mouse nasal mucosa in vivo.
2002,
Pubmed
O'Sullivan,
Cystic fibrosis.
2009,
Pubmed
Pankow,
A posttranslational modification code for CFTR maturation is altered in cystic fibrosis.
2019,
Pubmed
Pasyk,
A conserved region of the R domain of cystic fibrosis transmembrane conductance regulator is important in processing and function.
1998,
Pubmed
,
Xenbase
Perniss,
Hydrogen sulfide stimulates CFTR in Xenopus oocytes by activation of the cAMP/PKA signalling axis.
2017,
Pubmed
,
Xenbase
Pranke,
Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators.
2017,
Pubmed
Riordan,
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.
1989,
Pubmed
Saint-Criq,
Role of CFTR in epithelial physiology.
2017,
Pubmed
Seibert,
cAMP-dependent protein kinase-mediated phosphorylation of cystic fibrosis transmembrane conductance regulator residue Ser-753 and its role in channel activation.
1995,
Pubmed
Stevers,
Characterization and small-molecule stabilization of the multisite tandem binding between 14-3-3 and the R domain of CFTR.
2016,
Pubmed
Vankeerberghen,
Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator.
1998,
Pubmed
,
Xenbase
van Willigen,
Folding-function relationship of the most common cystic fibrosis-causing CFTR conductance mutants.
2019,
Pubmed
Veit,
From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.
2016,
Pubmed
Welzel,
Five novel mutations in the SCNN1A gene causing autosomal recessive pseudohypoaldosteronism type 1.
2013,
Pubmed
Wilschanski,
Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials.
2006,
Pubmed
Zhang,
Conformational Changes of CFTR upon Phosphorylation and ATP Binding.
2017,
Pubmed
