Alimentary TractResidual chloride secretion in intestinal tissue of ΔF508 homozygous twins and siblings with cystic fibrosis☆,☆☆
Section snippets
Subjects
Twin and sibling pairs with CF with different genotypes were enrolled for the European Cystic Fibrosis Twin and Sibling Study. For the study described here, only subjects homozygous for the CFTR gene mutation ΔF508 were selected. We invited 72 patients belonging to dizygous twin or sibling pairs and 26 patients belonging to monozygous twin pairs. Patients were investigated in or near their home countries at selected CF core centers in Hannover, Innsbruck, London, Rotterdam, and Verona.
Chloride-secretory response in CF intestine
Of the participating patients belonging to a sibling or dizygous twin pair, 49 responses to 8-bromo-cAMP + forskolin, 56 to carbachol, and 41 to histamine could be determined. Eighteen 8-bromo-cAMP + forskolin, 20 carbachol, and 14 histamine responses from participating patients of monozygous twin pairs were collected. The mean basal transepithelial resistance of the rectal biopsy specimens of our group of ΔF508 homozygous CF patients was 27 Ω·cm2. The mean basal Isc was 20 μA/cm2.
Patients for
Discussion
This study investigated the presence and frequency of chloride-secretory responses in the rectal tissue of ΔF508 homozygous CF twins and siblings upon stimulation with cAMP- and Ca2+-linked agonists, before and after incubation of the tissue with DIDS. Forty (73%) of the ΔF508 homozygotes expressed a cAMP-stimulated chloride-secretory response in their intestinal tissue. Because cAMP-regulated chloride conductance is indicative of CFTR,2, 3, 27 this finding suggests the presence of some active
Acknowledgements
The authors thank the collaborating patients, parents, physicians and scientists for their cooperation, particularly H. Ellemunter (Innsbruck), G. Mastella (Verona), S. Thomas (London), J. Versloot, H. Otten, and R. Samlal-Soedhoe (The Netherlands).
References (39)
- et al.
Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR)
Cell
(1992) - et al.
Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis
Gastroenterology
(1991) - et al.
Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl− channel proteins
Genomics
(1998) - et al.
Forskolin stimulates adenylate cyclase in human colonic crypts: interaction with VIP
Eur J Pharmacol
(1984) - et al.
Chloride transport in human proximal colonic apical membrane vesicles
Biochim Biophys Acta
(1996) - et al.
Regulation of ion transport by histamine in human colon
Eur J Pharmacol
(1995) - et al.
Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis
Cell
(1993) - et al.
Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis
Cell
(1990) - et al.
Higher bioelectric potentials due to decreased chloride absorption in the sweat glands of patients with cystic fibrosis
N Engl J Med
(1983) - et al.
Cyclic AMP–activated chloride channels in CFTR-transfected cystic fibrosis pancreatic epithelial cells
Am J Physiol
(1992)
Cystic fibrosis
Increased bioelectrical potential difference across respiratory epithelia in cystic fibrosis
N Engl J Med
Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis
Gut
Determinants of mild symptoms in cystic fibrosis patients: residual chloride secretion measured in rectal biopsies in relation to the genotype
J Clin Invest
Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor
Nat Genet
Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in Cftr(−/−) mice
Proc Natl Acad Sci U S A
The murine calcium-sensitive chloride channel (mCaCC) is widely expressed in secretory epithelia and in other select tissues
Histochem Cell Biol
Expression of delta F508 cystic fibrosis transmembrane conductance regulator protein and related chloride transport properties in the gallbladder epithelium from cystic fibrosis patients
Hepatology
Molecular cloning and transmembrane structure of hCLCA2 from human lung, trachea, and mammary gland
Am J Physiol
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Address requests for reprints to: Inez Bronsveld, Laboratory of Pediatrics, rm Ee-1500, Erasmus University Rotterdam, P.O. Box 1738, 3000 Rotterdam, The Netherlands. e-mail: [email protected]; fax: (31) 20-8706751.
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This work was executed as part of the European Cystic Fibrosis Twin and Sibling Study and supported by the BIOMED II program of the EU, the Deutsche Forschungsgemeinschaft, the Deutsche Fördergesellschaft für die Mukoviszidoseforschung eV, and the Mukoviszidose eV.