Measurements of CFTR-Mediated Cl- Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosis

Sousa, Marisa; Servidoni, Maria F.; Vinagre, Adriana M.; Ramalho, Anabela S.; Bonadia, Luciana C.; Felício, Verónica; Ribeiro, Maria A..; Uliyakina, Inna; Marson A, Fernando; Kmit, Arthur; Cardoso, Silvia R.; Ribeiro, José D.; Bertuzzo, Carmen S.; Sousa, Lisete; Kunzelmann, Karl; Ribeiro, Antônio F.; Amaral, Margarida D.

http://hdl.handle.net/10400.18/1534

Use this identifier to reference this record.

Name:	Description:	Size:	Format:
Sousa et al_2012_PLoSONE_0047708.pdf		526.16 KB	Adobe PDF	Download
Sousa et al_PLoSONE_0047708_Suppl_Methods.pdf	Dados suplementares	129.34 KB	Adobe PDF	Download

Send Feedback

Authors

Abstract(s)

BACKGROUND: Cystic 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 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.