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A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies
Nonsense mutations are present in 10% of patients with CF, produce a premature termination codon in CFTR mRNA causing early termination of translation, and lead to lack of CFTR function. There are no currently available animal models which contain a nonsense mutation in the endogenous Cftr locus tha...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010256/ https://www.ncbi.nlm.nih.gov/pubmed/29924856 http://dx.doi.org/10.1371/journal.pone.0199573 |
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author | McHugh, Daniel R. Steele, Miarasa S. Valerio, Dana M. Miron, Alexander Mann, Rachel J. LePage, David F. Conlon, Ronald A. Cotton, Calvin U. Drumm, Mitchell L. Hodges, Craig A. |
author_facet | McHugh, Daniel R. Steele, Miarasa S. Valerio, Dana M. Miron, Alexander Mann, Rachel J. LePage, David F. Conlon, Ronald A. Cotton, Calvin U. Drumm, Mitchell L. Hodges, Craig A. |
author_sort | McHugh, Daniel R. |
collection | PubMed |
description | Nonsense mutations are present in 10% of patients with CF, produce a premature termination codon in CFTR mRNA causing early termination of translation, and lead to lack of CFTR function. There are no currently available animal models which contain a nonsense mutation in the endogenous Cftr locus that can be utilized to test nonsense mutation therapies. In this study, we create a CF mouse model carrying the G542X nonsense mutation in Cftr using CRISPR/Cas9 gene editing. The G542X mouse model has reduced Cftr mRNA levels, demonstrates absence of CFTR function, and displays characteristic manifestations of CF mice such as reduced growth and intestinal obstruction. Importantly, CFTR restoration is observed in G542X intestinal organoids treated with G418, an aminoglycoside with translational readthrough capabilities. The G542X mouse model provides an invaluable resource for the identification of potential therapies of CF nonsense mutations as well as the assessment of in vivo effectiveness of these potential therapies targeting nonsense mutations. |
format | Online Article Text |
id | pubmed-6010256 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-60102562018-07-06 A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies McHugh, Daniel R. Steele, Miarasa S. Valerio, Dana M. Miron, Alexander Mann, Rachel J. LePage, David F. Conlon, Ronald A. Cotton, Calvin U. Drumm, Mitchell L. Hodges, Craig A. PLoS One Research Article Nonsense mutations are present in 10% of patients with CF, produce a premature termination codon in CFTR mRNA causing early termination of translation, and lead to lack of CFTR function. There are no currently available animal models which contain a nonsense mutation in the endogenous Cftr locus that can be utilized to test nonsense mutation therapies. In this study, we create a CF mouse model carrying the G542X nonsense mutation in Cftr using CRISPR/Cas9 gene editing. The G542X mouse model has reduced Cftr mRNA levels, demonstrates absence of CFTR function, and displays characteristic manifestations of CF mice such as reduced growth and intestinal obstruction. Importantly, CFTR restoration is observed in G542X intestinal organoids treated with G418, an aminoglycoside with translational readthrough capabilities. The G542X mouse model provides an invaluable resource for the identification of potential therapies of CF nonsense mutations as well as the assessment of in vivo effectiveness of these potential therapies targeting nonsense mutations. Public Library of Science 2018-06-20 /pmc/articles/PMC6010256/ /pubmed/29924856 http://dx.doi.org/10.1371/journal.pone.0199573 Text en © 2018 McHugh et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article McHugh, Daniel R. Steele, Miarasa S. Valerio, Dana M. Miron, Alexander Mann, Rachel J. LePage, David F. Conlon, Ronald A. Cotton, Calvin U. Drumm, Mitchell L. Hodges, Craig A. A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies |
title | A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies |
title_full | A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies |
title_fullStr | A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies |
title_full_unstemmed | A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies |
title_short | A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies |
title_sort | g542x cystic fibrosis mouse model for examining nonsense mutation directed therapies |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010256/ https://www.ncbi.nlm.nih.gov/pubmed/29924856 http://dx.doi.org/10.1371/journal.pone.0199573 |
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