Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis.
<h4>Background</h4>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 var...
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oai:doaj.org-article:2860c930e59242669d87fa4093d5ef952021-11-18T08:11:38ZMeasurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis.1932-620310.1371/journal.pone.0047708https://doaj.org/article/2860c930e59242669d87fa4093d5ef952012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23082198/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Marisa SousaMaria F ServidoniAdriana M VinagreAnabela S RamalhoLuciana C BonadiaVerónica FelícioMaria A RibeiroInna UliyakinaFernando A MarsonArthur KmitSilvia R CardosoJosé D RibeiroCarmen S BertuzzoLisete SousaKarl KunzelmannAntônio F RibeiroMargarida D AmaralPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e47708 (2012) |
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Medicine R Science Q |
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Medicine R Science Q Marisa Sousa Maria F Servidoni Adriana M Vinagre Anabela S Ramalho Luciana C Bonadia Verónica Felício Maria A Ribeiro Inna Uliyakina Fernando A Marson Arthur Kmit Silvia R Cardoso José D Ribeiro Carmen S Bertuzzo Lisete Sousa Karl Kunzelmann Antônio F Ribeiro Margarida D Amaral Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. |
| description |
<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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. |
| format |
article |
| author |
Marisa Sousa Maria F Servidoni Adriana M Vinagre Anabela S Ramalho Luciana C Bonadia Verónica Felício Maria A Ribeiro Inna Uliyakina Fernando A Marson Arthur Kmit Silvia R Cardoso José D Ribeiro Carmen S Bertuzzo Lisete Sousa Karl Kunzelmann Antônio F Ribeiro Margarida D Amaral |
| author_facet |
Marisa Sousa Maria F Servidoni Adriana M Vinagre Anabela S Ramalho Luciana C Bonadia Verónica Felício Maria A Ribeiro Inna Uliyakina Fernando A Marson Arthur Kmit Silvia R Cardoso José D Ribeiro Carmen S Bertuzzo Lisete Sousa Karl Kunzelmann Antônio F Ribeiro Margarida D Amaral |
| author_sort |
Marisa Sousa |
| title |
Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. |
| title_short |
Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. |
| title_full |
Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. |
| title_fullStr |
Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. |
| title_full_unstemmed |
Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. |
| title_sort |
measurements of cftr-mediated cl- secretion in human rectal biopsies constitute a robust biomarker for cystic fibrosis diagnosis and prognosis. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/2860c930e59242669d87fa4093d5ef95 |
| work_keys_str_mv |
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