학술논문
CFTR function is impaired in a subset of patients with pancreatitis carrying rare CFTR variants.
Document Type
Academic Journal
Author
Angyal D; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, P.O. Box 2040, 3000, CA, Rotterdam, the Netherlands.; Kleinfelder K; Department of Medicine, University of Verona, Division of General Pathology, Verona, Italy.; Ciciriello F; Cystic Fibrosis Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.; Groeneweg TA; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, P.O. Box 2040, 3000, CA, Rotterdam, the Netherlands.; De Marchi G; Gastroenterology Unit, Department of Medicine, Borgo Roma Hospital, Piazzale L.A. Scuro 10, 37134, Verona, Italy.; de Pretis N; Gastroenterology Unit, Department of Medicine, Borgo Roma Hospital, Piazzale L.A. Scuro 10, 37134, Verona, Italy.; Bernardoni L; Gastroenterology Unit, Department of Medicine, Borgo Roma Hospital, Piazzale L.A. Scuro 10, 37134, Verona, Italy.; Rodella L; Endoscopy Surgery Unit, Azienda Ospedaliera Universitaria Integrata Verona, 37126, Verona, Italy.; Tomba F; Endoscopy Surgery Unit, Azienda Ospedaliera Universitaria Integrata Verona, 37126, Verona, Italy.; De Angelis P; Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.; Surace C; Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Viale di San Paolo 15, 00146, Rome, Italy.; Pintani E; Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.; Alghisi F; Cystic Fibrosis Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.; de Jonge HR; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, P.O. Box 2040, 3000, CA, Rotterdam, the Netherlands.; Melotti P; Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.; Sorio C; Department of Medicine, University of Verona, Division of General Pathology, Verona, Italy.; Lucidi V; Cystic Fibrosis Unit, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.; Bijvelds MJC; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, P.O. Box 2040, 3000, CA, Rotterdam, the Netherlands. Electronic address: m.bijvelds@erasmusmc.nl.; Frulloni L; Gastroenterology Unit, Department of Medicine, Borgo Roma Hospital, Piazzale L.A. Scuro 10, 37134, Verona, Italy.
Source
Publisher: Country of Publication: Switzerland NLM ID: 100966936 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1424-3911 (Electronic) Linking ISSN: 14243903 NLM ISO Abbreviation: Pancreatology Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Many affected by pancreatitis harbor rare variants of the cystic fibrosis (CF) gene, CFTR, which encodes an epithelial chloride/bicarbonate channel. We investigated CFTR function and the effect of CFTR modulator drugs in pancreatitis patients carrying CFTR variants.
Methods: Next-generation sequencing was performed to identify CFTR variants. Sweat tests and nasal potential difference (NPD) assays were performed to assess CFTR function in vivo. Intestinal current measurement (ICM) was performed on rectal biopsies. Patient-derived intestinal epithelial monolayers were used to evaluate chloride and bicarbonate transport and the effects of a CFTR modulator combination: elexacaftor, tezacaftor and ivacaftor (ETI).
Results: Of 32 pancreatitis patients carrying CFTR variants, three had CF-causing mutations on both alleles and yielded CF-typical sweat test, NPD and ICM results. Fourteen subjects showed a more modest elevation in sweat chloride levels, including three that were provisionally diagnosed with CF. ICM indicated impaired CFTR function in nine out of 17 non-CF subjects tested. This group of nine included five carrying a wild type CFTR allele. In epithelial monolayers, a reduction in CFTR-dependent chloride transport was found in six out of 14 subjects tested, whereas bicarbonate secretion was reduced in only one individual. In epithelial monolayers of four of these six subjects, ETI improved CFTR function.
Conclusions: CFTR function is impaired in a subset of pancreatitis patients carrying CFTR variants. Mutations outside the CFTR locus may contribute to the anion transport defect. Bioassays on patient-derived intestinal tissue and organoids can be used to detect such defects and to assess the effect of CFTR modulators.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Methods: Next-generation sequencing was performed to identify CFTR variants. Sweat tests and nasal potential difference (NPD) assays were performed to assess CFTR function in vivo. Intestinal current measurement (ICM) was performed on rectal biopsies. Patient-derived intestinal epithelial monolayers were used to evaluate chloride and bicarbonate transport and the effects of a CFTR modulator combination: elexacaftor, tezacaftor and ivacaftor (ETI).
Results: Of 32 pancreatitis patients carrying CFTR variants, three had CF-causing mutations on both alleles and yielded CF-typical sweat test, NPD and ICM results. Fourteen subjects showed a more modest elevation in sweat chloride levels, including three that were provisionally diagnosed with CF. ICM indicated impaired CFTR function in nine out of 17 non-CF subjects tested. This group of nine included five carrying a wild type CFTR allele. In epithelial monolayers, a reduction in CFTR-dependent chloride transport was found in six out of 14 subjects tested, whereas bicarbonate secretion was reduced in only one individual. In epithelial monolayers of four of these six subjects, ETI improved CFTR function.
Conclusions: CFTR function is impaired in a subset of pancreatitis patients carrying CFTR variants. Mutations outside the CFTR locus may contribute to the anion transport defect. Bioassays on patient-derived intestinal tissue and organoids can be used to detect such defects and to assess the effect of CFTR modulators.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)