Clinical and molecular characterization of the R751L-CFTR mutation

Area of Science:

• Genetics and Molecular Biology
• Respiratory Medicine
• Cell Physiology

Background:

• Cystic fibrosis (CF) is caused by mutations in the CFTR gene, leading to severe respiratory issues.
• The R751L mutation is a rare CFTR variant with limited characterization.
• Understanding CFTR mutations is crucial for developing effective CF treatments.

Purpose of the Study:

• To investigate the clinical and molecular characteristics of the R751L CFTR mutation.
• To assess the functional impact of R751L-CFTR in relevant biological models.
• To correlate genotype with phenotype in individuals with the R751L mutation.

Main Methods:

• Clinical data analysis from three R751L heterozygote individuals.
• Functional assessment of R751L-CFTR in human bronchial epithelial (HBE) cultures and Xenopus oocytes.
• Investigation of R751L-CFTR molecular properties with CFTR modulators.

Main Results:

• Individuals with R751L exhibited elevated sweat chloride levels but a mild clinical CF phenotype.
• R751L-CFTR showed normal folding, cell surface transport, and channel function in Xenopus oocytes.
• Reduced chloride secretion and sodium absorption were observed in F508del/R751L HBEs compared to non-CF HBEs.

Conclusions:

• The R751L CFTR mutation is associated with reduced sodium chloride absorption but possesses WT-like functional properties.
• This study provides the first combined clinical and functional characterization of R751L-CFTR.
• Findings may inform clinical management strategies and highlight the need to investigate non-CFTR factors for elevated sweat chloride and reduced HBE secretion.