Clinical and molecular characterization of S1118F-CFTR

Background: Cystic fibrosis is a lethal autosomal recessive disorder usually associated with lung disease, pancreatic insufficiency and high sweat chloride levels. Clinical Case: A patient admitted to Le Bonheur Children's Medical Center (LBCMC, Memphis, TN) showed symptoms of meconium ileus which required exploratory laparotomy, bowel resection and ileostomy. Genotyping showed ΔF508/I1027T on one chromosome and S1118F on the other. Sweat testing on three different occasions gave negative and intermediate results (22.7, 24.6 mmol/L; 55.1, 58.6 mmol/L and 55.1, 58 mmol/L) and pancreatic elastase testing showed normal levels. Objective: To characterize S1118F-CFTR mutation at a molecular level to help understand the associated CF-phenotype. Methods: Molecular characterization of S1118F-CFTR mutant was studied in HEK-293 cells at 37°C. Various biochemical methods such as Western blotting, real-time PCR, Pulse chase labeling and iodide efflux assay were employed. Results: S1118F-CFTR makes less than 10-15% of mature CFTR (band C) compared to WT-CFTR. The mRNA levels of S1118F-CFTR and WT-CFTR are comparable. S1118F-CFTR is functional but shows about 10-15% of WT-CFTR activity. S1118F-CFTR shows impaired maturation and CF-correctors can increase the amount of mature and functional CFTR by three- to fourfold. Conclusion: S1118F-CFTR shows impaired maturation and an individual with S1118F-CFTR paired with ΔF508- CFTRexhibits atypicalCFsymptomswith intermediate sweat chloride level and meconium ileus despite documented pancreatic sufficiency.