Clinical and molecular characterization of S1118F-CFTR

Himabindu Penmatsa, Carla A. Frederick, Sunitha Nekkalapu, Veronica G. Conoley, Weiqiang Zhang, Chunying Li, John Kappes, Dennis C. Stokes, Anjaparavanda P. Naren

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1003-1009
Number of pages7
JournalPediatric Pulmonology
Volume44
Issue number10
DOIs
StatePublished - Oct 1 2009

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Sweat
Meconium
Ileus
Chlorides
Exocrine Pancreatic Insufficiency
Ileostomy
HEK293 Cells
Pancreatic Elastase
Iodides
Cystic Fibrosis
Laparotomy
Lung Diseases
Real-Time Polymerase Chain Reaction
Chromosomes
Western Blotting
Phenotype
Messenger RNA
Mutation

All Science Journal Classification (ASJC) codes

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine

Cite this

Penmatsa, H., Frederick, C. A., Nekkalapu, S., Conoley, V. G., Zhang, W., Li, C., ... Naren, A. P. (2009). Clinical and molecular characterization of S1118F-CFTR. Pediatric Pulmonology, 44(10), 1003-1009. https://doi.org/10.1002/ppul.21092

Clinical and molecular characterization of S1118F-CFTR. / Penmatsa, Himabindu; Frederick, Carla A.; Nekkalapu, Sunitha; Conoley, Veronica G.; Zhang, Weiqiang; Li, Chunying; Kappes, John; Stokes, Dennis C.; Naren, Anjaparavanda P.

In: Pediatric Pulmonology, Vol. 44, No. 10, 01.10.2009, p. 1003-1009.

Research output: Contribution to journalArticle

Penmatsa, H, Frederick, CA, Nekkalapu, S, Conoley, VG, Zhang, W, Li, C, Kappes, J, Stokes, DC & Naren, AP 2009, 'Clinical and molecular characterization of S1118F-CFTR', Pediatric Pulmonology, vol. 44, no. 10, pp. 1003-1009. https://doi.org/10.1002/ppul.21092
Penmatsa H, Frederick CA, Nekkalapu S, Conoley VG, Zhang W, Li C et al. Clinical and molecular characterization of S1118F-CFTR. Pediatric Pulmonology. 2009 Oct 1;44(10):1003-1009. https://doi.org/10.1002/ppul.21092
Penmatsa, Himabindu ; Frederick, Carla A. ; Nekkalapu, Sunitha ; Conoley, Veronica G. ; Zhang, Weiqiang ; Li, Chunying ; Kappes, John ; Stokes, Dennis C. ; Naren, Anjaparavanda P. / Clinical and molecular characterization of S1118F-CFTR. In: Pediatric Pulmonology. 2009 ; Vol. 44, No. 10. pp. 1003-1009.
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abstract = "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.",
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AB - 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.

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