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Type: Artigo de periódico
Title: Measurements of CFTR-Mediated Cl- Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosis
Author: Sousa, M
Servidoni, MF
Vinagre, AM
Ramalho, AS
Bonadia, LC
Felicio, V
Ribeiro, MA
Uliyakina, I
Marson, FA
Kmit, A
Cardoso, SR
Ribeiro, JD
Bertuzzo, CS
Sousa, L
Kunzelmann, K
Ribeiro, AF
Amaral, MD
Abstract: Background: Cystic Fibrosis (CF) is caused by similar to 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 Findings: To 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/Significance: Determination 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.
Country: EUA
Editor: Public Library Science
Citation: Plos One. Public Library Science, v. 7, n. 10, 2012.
Rights: aberto
Identifier DOI: 10.1371/journal.pone.0047708
Date Issue: 2012
Appears in Collections:Unicamp - Artigos e Outros Documentos

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