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

2012-10Journal article Open access
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dc.contributor.authorSousa, Marisa
dc.contributor.authorServidoni, Maria F.
dc.contributor.authorVinagre, Adriana M.
dc.contributor.authorRamalho, Anabela S.
dc.contributor.authorBonadia, Luciana C.
dc.contributor.authorFelício, Verónica
dc.contributor.authorRibeiro, Maria A..
dc.contributor.authorUliyakina, Inna
dc.contributor.authorMarson A, Fernando
dc.contributor.authorKmit, Arthur
dc.contributor.authorCardoso, Silvia R.
dc.contributor.authorRibeiro, José D.
dc.contributor.authorBertuzzo, Carmen S.
dc.contributor.authorSousa, Lisete
dc.contributor.authorKunzelmann, Karl
dc.contributor.authorRibeiro, Antônio F.
dc.contributor.authorAmaral, Margarida D.
dc.date.accessioned2013-03-22T12:05:45Z
dc.date.available2013-03-22T12:05:45Z
dc.date.issued2012-10
dc.description.abstractBACKGROUND: 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.por
dc.description.sponsorshipThis work was supported by grants TargetScreen2 (EU/FP6/LSH/2005/037365), PIC/IC/83103/2007; PTDC/MAT/118335/2010; PEstOE/BIA/UI4046/2011 (to BioFIG) and PEstOE/MAT/UI0006/2011 (to CEAUL) from FCT (Portugal); and FAPESP (SPRF, Brazil), CNPq (40.8924/2006/3, Brazil) and Mukoviszidose e.V. S02/10 (Germany). MS and IU are recipients of SFRH/BD/35936/2007 and SFRH/BD/69180/2010 PhD fellowships (FCT, Portugal), respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.por
dc.identifier.citationPLoS One. 2012;7(10):e47708. doi: 10.1371/journal.pone.0047708. Epub 2012 Oct 17por
dc.identifier.issn1932-6203
dc.identifier.otherdoi: 10.1371/journal.pone.0047708
dc.identifier.urihttp://hdl.handle.net/10400.18/1534
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherDominik Hartl, University of Tu¨ bingen, Germanypor
dc.relation.publisherversionhttp://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0047708por
dc.subjectFibrose Quísticapor
dc.subjectCFTRpor
dc.subjectDoenças Genéticaspor
dc.titleMeasurements of CFTR-Mediated Cl- Secretion in Human Rectal Biopsies Constitute a Robust Biomarker for Cystic Fibrosis Diagnosis and Prognosispor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.startPagee47708por
oaire.citation.titlePLoS Onepor
oaire.citation.volume7(10)por
rcaap.rightsopenAccesspor
rcaap.typearticlepor

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