Clinical and molecular characterization of the R751L-CFTR mutation

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)L288-L300
Number of pages13
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume320
Issue number2
DOIs
Publication statusPublished - 18 Feb 2021

Keywords

  • Amino Acid Substitution
  • Animals
  • Bronchi/metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator/genetics
  • Cystic Fibrosis/genetics
  • Epithelial Cells/metabolism
  • Female
  • Humans
  • Male
  • Mutation, Missense
  • Sodium Chloride/metabolism
  • Xenopus laevis

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