Abstract
BackgroundCystic Fibrosis (CF) is caused by ∼1,900 mutations in the CF transmembrane conductance regulator (CFTR) gene encoding for a cAMP-regulated chloride (Cl−) channel expressed in several epithelia. Clinical features are dominated by respiratory symptoms, but there is variable organ involvement thus causing diagnostic dilemmas, especially for non-classic cases.Methodology/Principal FindingsTo further establish measurement of CFTR function as a sensitive and robust biomarker for diagnosis and prognosis of CF, we herein assessed cholinergic and cAMP-CFTR-mediated Cl− secretion in 524 freshly excised rectal biopsies from 118 individuals, including patients with confirmed CF clinical diagnosis (n = 51), individuals with clinical CF suspicion (n = 49) and age-matched non-CF controls (n = 18). Conclusive measurements were obtained for 96% of cases. Patients with “Classic CF”, presenting earlier onset of symptoms, pancreatic insufficiency, severe lung disease and low Shwachman-Kulczycki scores were found to lack CFTR-mediated Cl− secretion (<5%). Individuals with milder CF disease presented residual CFTR-mediated Cl− secretion (10–57%) and non-CF controls show CFTR-mediated Cl− secretion ≥30–35% and data evidenced good correlations with various clinical parameters. Finally, comparison of these values with those in “CF suspicion” individuals allowed to confirm CF in 16/49 individuals (33%) and exclude it in 28/49 (57%). Statistical discriminant analyses showed that colonic measurements of CFTR-mediated Cl− secretion are the best discriminator among Classic/Non-Classic CF and non-CF groups.Conclusions/SignificanceDetermination of CFTR-mediated Cl− secretion in rectal biopsies is demonstrated here to be a sensitive, reproducible and robust predictive biomarker for the diagnosis and prognosis of CF. The method also has very high potential for (pre-)clinical trials of CFTR-modulator therapies.
Highlights
Cystic Fibrosis (CF), the most common severe autosomal recessive disease in Caucasians, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene [1,2,3] which encodes a cAMP-regulated chloride (Cl2) channel expressed at the apical membrane of epithelial cells to control salt and water transport [4].Clinically, CF is characterized by multiple manifestations in different organs, but is dominated by the respiratory disease, the main cause of morbidity and mortality
The wide spectrum of CF phenotypes, high variability of CF lung disease, the uncertainfunction of many rare CFTR mutations together with increasing numbers of asymptomatic patients identified in recent newborn CF screens, have posed major challenges to clinicians for the establishment of CF diagnoses and prognosis [8,10,11]
To evaluate the robustness of colonic CFTR-mediated Cl2 secretion as a diagnosis/prognosis biomarker and help overcoming such difficulties, we assessed CFTRfunction ex vivo in 524 rectal biopsies from 118 individuals, including the largest cohort of CF patients ever analysed by this approach (n = 51), a non-CF group (n = 18) and individuals with clinical CF suspicion to confirm/exclude a CF diagnosis (n = 49)
Summary
Cystic Fibrosis (CF), the most common severe autosomal recessive disease in Caucasians, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene [1,2,3] which encodes a cAMP-regulated chloride (Cl2) channel expressed at the apical membrane of epithelial cells to control salt and water transport [4]. CF is characterized by multiple manifestations in different organs, but is dominated by the respiratory disease, the main cause of morbidity and mortality. Cystic Fibrosis (CF) is caused by ,1,900 mutations in the CF transmembrane conductance regulator (CFTR) gene encoding for a cAMP-regulated chloride (Cl2) channel expressed in several epithelia. Clinical features are dominated by respiratory symptoms, but there is variable organ involvement causing diagnostic dilemmas, especially for non-classic cases
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