Gastroenterology

Gastroenterology

Volume 127, Issue 4, October 2004, Pages 1085-1095
Gastroenterology

Clinical-alimentary tract
CFTR Cl channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis

https://doi.org/10.1053/j.gastro.2004.07.006Get rights and content

Background & Aims: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. Methods: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-ΔF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl secretion with patients in whom Cl secretion was absent. Results: Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of ∼12%–54% of controls. Conclusions: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.

Section snippets

Patients

The study was approved by the Ethical Committee at the University Hospitals of Freiburg, Lisbon, and Vienna, and all patients gave their written informed consent. For children under 18, parents obtained detailed information and gave their signed informed consent. Forty-five CF patients who carry at least 1 non-ΔF508 mutation (29 PI, 16 PS; mean age, 16.5 ± 1.8 years; range, 5 months–47 years), 19 age-matched healthy controls (15.6 ± 3.7 years; range, 10 months–55 years), and 13 age-matched

Assessment of CFTR Cl channel function

CFTR function was measured as cAMP-mediated Cl secretion in freshly excised rectal biopsy specimens from 45 CF patients who have at least 1 non-ΔF508 mutation, 19 age-matched controls, and 13 ΔF508 carriers. The magnitude of CFTR-mediated anion secretion was assessed after inhibition of endogenous cAMP formation by indomethacin (10 μmol/L, basolateral, 60 min) and electrogenic Na+ absorption by amiloride (10 μmol/L, luminal). Under these conditions, Vte and Isc approached 0 and Rte was similar

Discussion

The elucidation of the relationship between CFTR protein function and phenotypic traits for specific CFTR mutations is important for the understanding of CF pathophysiology and for the development of novel therapeutic strategies for patients with CF. Genotype-phenotype correlation studies estimated that ∼15%–20% of CF patients express mild mutations that confer PS.2, 15, 23 The most frequent CFTR mutation, ΔF508, accounts for ∼66% of CF alleles and results in the loss of mature CFTR protein and

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    • Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A&gt;G

      2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
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      Altogether, these data are consistent with S955P, being a class III (gating) mutation. The fact that in organoids it also appears at much lower levels than wt-CFTR (Fig. 2C) suggests that S955P-CFTR is unstable, thus possibly also being a class VI mutation [6]. Of note, another example of a mixed class III/VI mutations is Q1412X [21].

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    S.H. and T.G. contributed equally to this work.

    Supported by the Mukoviszidose e.V., the Deutsche Forschungsgemeinschaft (DFG MA 2081/2-1 and KU 1228/1-1), the Zentrum Klinische Forschung 1 University of Freiburg (ZKF1, A2), and by POCTI/35737/MGI/2000 and POCTI/MGI/47382/2002 research grants (Fundacao Ciencia Tecnologia, Portugal).

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