Clinical and molecular characterization of S1118F‐CFTR

AbstractBackgroundCystic fibrosis is a lethal autosomal recessive disorder usually associated with lung disease, pancreatic insufficiency and high sweat chloride levels.Clinical CaseA 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.ObjectiveTo characterize S1118F‐CFTR mutation at a molecular level to help understand the associated CF‐phenotype.MethodsMolecular 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.ResultsS1118F‐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.ConclusionS1118F‐CFTR shows impaired maturation and an individual with S1118F‐CFTR paired with ΔF508‐CFTR exhibits atypical CF symptoms with intermediate sweat chloride level and meconium ileus despite documented pancreatic sufficiency. Pediatr Pulmonol. 2009; 44:1003–1009. ©2009 Wiley‐Liss, Inc.