Clinical-alimentary tractCFTR Cl− channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis
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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2021, Biomedicine and PharmacotherapyOrganoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A>G
2020, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :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].
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).