A G542X cystic fibrosis mouse model for examining nonsense mutation directed therapies
| Autor: | Ronald A. Conlon, Calvin U. Cotton, Rachel J. Mann, Mitchell L. Drumm, David F. LePage, Dana M. Valerio, Alexander Miron, M. Steele, Craig A. Hodges, Daniel R. McHugh |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Cystic Fibrosis Pulmonology Cystic Fibrosis Transmembrane Conductance Regulator lcsh:Medicine Artificial Gene Amplification and Extension Cystic fibrosis Polymerase Chain Reaction Tissue Culture Techniques Genome editing Medicine and Health Sciences CRISPR Organ Cultures lcsh:Science Cells Cultured Multidisciplinary Insertion Mutation Translational readthrough Nonsense Mutation Animal Models respiratory system Organoids Intestines Experimental Organism Systems Genetic Diseases Codon Nonsense Female Biological Cultures Anatomy Research Article congenital hereditary and neonatal diseases and abnormalities Nonsense mutation Mouse Models Mice Transgenic Biology Research and Analysis Methods 03 medical and health sciences Model Organisms Autosomal Recessive Diseases medicine Genetics Animals Insertion RNA Messenger Molecular Biology Techniques Molecular Biology Clinical Genetics Messenger RNA Cas9 lcsh:R Biology and Life Sciences Genetic Therapy medicine.disease Fibrosis Gastrointestinal Tract Mice Inbred C57BL Disease Models Animal 030104 developmental biology Mutation Cancer research lcsh:Q CRISPR-Cas Systems Digestive System Developmental Biology |
| Zdroj: | PLoS ONE, Vol 13, Iss 6, p e0199573 (2018) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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