Clinical-alimentary tractThe ΔF508 mutation results in loss of CFTR function and mature protein in native human colon☆
Section snippets
Patients
Rectal biopsy specimens were studied from 12 ΔF508 homozygous patients with CF (ΔF/ΔF; mean age, 10.4 ± 2.8 years; range, 1 month to 32 years; 7 male patients and 5 female patients), 15 age-matched normal individuals (wt/wt; mean age, 8.9 ± 1.4 years; range, 2–22 years; 9 male patients and 6 female patients), and 8 ΔF508 heterozygous subjects (ΔF/wt; mean age, 8.8 ± 1.8 years; range, 3–18 years; 5 male patients and 3 female patients). All ΔF508 homozygous patients with CF had chronic lung
cAMP-dependent and cholinergic Cl− secretion in normal and ΔF508 homozygous CF rectal tissues
In freshly excised normal colonic epithelia, CFTR-mediated secretion is at approximately 50% maximal activity under basal conditions due to endogenous cellular cAMP accumulation.22, 24 To assess the absolute magnitude of CFTR-mediated secretion, endogenous cAMP formation was inhibited by pretreatment with indomethacin (10 μmol/L, basolateral, 60 minutes) and electrogenic Na+ absorption was eliminated by exposure to amiloride (10 μmol/L, luminal). As previously reported for patients with CF with
Discussion
The elucidation of the molecular and cellular fate of ΔF508 CFTR in native epithelial tissues is crucial for the development of therapeutic strategies for the treatment of patients with CF. In contrast to studies of ΔF508 maturation and function in heterologous cells,5, 6, 7, 8, 9 the data describing ΔF508 maturation and function in native epithelia are discordant.12, 13, 14, 15, 16, 17, 18, 19 In an attempt to reconcile these conflicting data, we studied a native epithelium affected by CF
Acknowledgements
The authors thank the patients with CF as well as the volunteers for their participation in this study, Dr. Peter Greiner for performing rectoscopy procedures, Dr. Joachim Kuehr and Dr. Tanja Gonska for clinical evaluation of patients with CF, Dr. Sherif Gabriel for the kind gift of the MTE18 and MTE18-CFTR cells, Tracy Eldred and Kim Burns for tissue processing, Transgene (France) for the kind gift of CFTR antibody MATG1061, and Lisa Brown for editing of the manuscript.
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Cited by (0)
- ☆
Supported by the Mukoviszidose e.V. and the Deutsche Forschungsgemeinschaft (DFG MA 2081/2-1) (to M.M.), the Cystic Fibrosis Foundation (KREDAO0110) and the Mary Lynn Richardson Fund (to S.M.K.), and National Institutes of Health grants DK51870 (to J.R.R.) and HL34322 and HL60280 (to R.C.B.).
- 1
M.M. and S.M.K. contributed equally to this work.
- 2
J.R.R. and R.C.B. contributed equally to this work as senior authors.