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Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Cystic fibrosis, the most common autosomal recessive disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated chloride and bicarbonate channel that regulates ion and water transport in secretory epithelia. A...

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Detalles Bibliográficos
Autores principales: Farinha, Carlos M., Callebaut, Isabelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251585/
https://www.ncbi.nlm.nih.gov/pubmed/35707985
http://dx.doi.org/10.1042/BSR20212006
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author Farinha, Carlos M.
Callebaut, Isabelle
author_facet Farinha, Carlos M.
Callebaut, Isabelle
author_sort Farinha, Carlos M.
collection PubMed
description Cystic fibrosis, the most common autosomal recessive disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated chloride and bicarbonate channel that regulates ion and water transport in secretory epithelia. Although all mutations lead to the lack or reduction in channel function, the mechanisms through which this occurs are diverse – ranging from lack of full-length mRNA, reduced mRNA levels, impaired folding and trafficking, targeting to degradation, decreased gating or conductance, and reduced protein levels to decreased half-life at the plasma membrane. Here, we review the different molecular mechanisms that cause cystic fibrosis and detail how these differences identify theratypes that can inform the use of directed therapies aiming at correcting the basic defect. In summary, we travel through CFTR life cycle from the gene to function, identifying what can go wrong and what can be targeted in terms of the different types of therapeutic approaches.
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spelling pubmed-92515852022-07-14 Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy Farinha, Carlos M. Callebaut, Isabelle Biosci Rep Cell Membranes, Excitation & Transport Cystic fibrosis, the most common autosomal recessive disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-activated chloride and bicarbonate channel that regulates ion and water transport in secretory epithelia. Although all mutations lead to the lack or reduction in channel function, the mechanisms through which this occurs are diverse – ranging from lack of full-length mRNA, reduced mRNA levels, impaired folding and trafficking, targeting to degradation, decreased gating or conductance, and reduced protein levels to decreased half-life at the plasma membrane. Here, we review the different molecular mechanisms that cause cystic fibrosis and detail how these differences identify theratypes that can inform the use of directed therapies aiming at correcting the basic defect. In summary, we travel through CFTR life cycle from the gene to function, identifying what can go wrong and what can be targeted in terms of the different types of therapeutic approaches. Portland Press Ltd. 2022-07-01 /pmc/articles/PMC9251585/ /pubmed/35707985 http://dx.doi.org/10.1042/BSR20212006 Text en © 2022 The Author(s). https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Cell Membranes, Excitation & Transport
Farinha, Carlos M.
Callebaut, Isabelle
Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy
title Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy
title_full Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy
title_fullStr Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy
title_full_unstemmed Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy
title_short Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy
title_sort molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy
topic Cell Membranes, Excitation & Transport
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251585/
https://www.ncbi.nlm.nih.gov/pubmed/35707985
http://dx.doi.org/10.1042/BSR20212006
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