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Clinical and molecular characterization of the R751L-CFTR mutation

  • Cysticfibrosis (CF) arises from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in progressiveand life-limiting respiratory disease. R751L is a rare CFTR mutation that is poorly characterized. Our aims were to describe theclinical and molecular phenotypes associated with R751L. Relevant clinical data were collected from three heterozygote individu-als harboring R751L (2 patients with G551D/R751L and 1 with F508del/R751L). Assessment of R751L-CFTR function was made inprimary human bronchial epithelial cultures (HBEs) andXenopusoocytes. Molecular properties of R751L-CFTR were investigatedin the presence of known CFTR modulators. Although sweat chloride was elevated in all three patients, the clinical phenotypeassociated with R751L was mild. Chloride secretion in F508del/R751L HBEs was reduced compared with non-CF HBEs and asso-ciated with a reduction in sodium absorption by the epithelial sodium channel (ENaC). However, R751L-CFTR function inXenopusoocytes, 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 thefirst report of R751L-CFTR that combines clinical phenotype with characterization of functional and biological proper-ties 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 al-ternative non-CFTR factors, which require further investigation.

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Document Type:Article
Author:Iram J. Haq, Mike Althaus, Aaron Ions Gardner, Hui Ying Yeoh, Urjita Joshi, Vinciane Saint-Criq, Bernard Verdon, Jennifer Townshend, Christopher O'Brien, Mahfud Ben-Hamida, Matthew Thomas, Stephen Bourke, Peter van der Sluijs, Ineke Braakman, Chris Ward, Michael A. Gray, Malcolm Brodlie
Parent Title (English):American Journal of Physiology: Lung Cellular and Molecular Physiology
First Page:L288
Last Page:L300
Publisher:American Physiological Society
Place of publication:Bethesda, MD, USA
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2020/12/09
Copyright:Copyright ©2021 The Authors. Licensed under Creative Commons Attribution CC-BY 4.0.
Funding:This work was supported by a Wellcome Trust ClinicalResearch Training Fellowship [203520/Z/16/Z] to I.J.H; a Medical Research Council Clinician Scientist Fellowship [MR/M008797/1]to M.B; CF Trust Strategic Research Center grants [SRC003] and[SRC013] to M.A.G., C.W., and M.B.; the Netherlands Organizationfor Health Research and Development [ZonMw TOP 40-00812-98-14103], Dutch Research Council [LIFT 731.017.404], and CFF[BRAAKM14XX0] for the P.vdS.-I.B. Laboratory. The research was supported by the National Institute for Health Research (NIHR)Newcastle Biomedical Research Center based at NewcastleHospitals NHS Foundation Trust and Newcastle University.
Keyword:CFTR mutations; R751L; cysticfibrosis; primary airway epithelial cells
Departments, institutes and facilities:Fachbereich Angewandte Naturwissenschaften
Institut für funktionale Gen-Analytik (IFGA)
Dewey Decimal Classification (DDC):6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 616 Krankheiten
Entry in this database:2020/12/12
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International