Consequences of Lmna Exon 4 Mutations in Myoblast Function

Autor:	Gisèle Bonne, Anne Bertrand, Carolina Epifano, Javier Ramón-Azcón, Alberto Martín, Albert G. Castaño, Miguel Ángel Rodríguez-Milla, Déborah Gómez-Domínguez, Fernando de Miguel, Borja Vilaplana-Martí, Sandra Amarilla-Quintana, Ignacio Pérez de Castro
Přispěvatelé:	Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Instituto de Salud Carlos III [Madrid] (ISC), Universidad Europea de Madrid, Institute for Bioengineering of Catalonia [Barcelona] (IBEC), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institució Catalana de Recerca i Estudis Avançats (ICREA), Centre de recherche en Myologie – U974 SU-INSERM
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	life_sciences_other 0301 basic medicine Laminopathy [SDV]Life Sciences [q-bio] Mutant laminopathy medicine.disease_cause Muscle Development LMNA Myoblasts Exon Mice 0302 clinical medicine Tecnología médica lcsh:QH301-705.5 Genetics Mutation integumentary system Cell Differentiation General Medicine nuclear envelope Exons Lamin Type A 030220 oncology & carcinogenesis CRISPR Female C2C12 Microtubule-Associated Proteins Subcellular Fractions congenital hereditary and neonatal diseases and abnormalities Cell Nucleus Shape Membrana nuclear Nuclear Envelope MAP Kinase Signaling System Telomere-Binding Proteins Biology Distrofias musculares Article Cell Line 03 medical and health sciences medicine Animals Protein kinase B Cell Nucleus Biología celular Base Sequence Membrane Proteins medicine.disease Genética Clone Cells 030104 developmental biology lcsh:Biology (General) Lamin DNA Damage
Zdroj:	Cells Repisalud Instituto de Salud Carlos III (ISCIII) Cells, MDPI, 2020, 9 (5), pp.1286. ⟨10.3390/cells9051286⟩ Cells, Vol 9, Iss 1286, p 1286 (2020) ABACUS. Repositorio de Producción Científica Universidad Europea (UEM) Volume 9 Issue 5
ISSN:	2073-4409
Popis:	Laminopathies are causally associated with mutations on the Lamin A/C gene (LMNA). To date, more than 400 mutations in LMNA have been reported in patients. These mutations are widely distributed throughout the entire gene and are associated with a wide range of phenotypes. Unfortunately, little is known about the mechanisms underlying the effect of the majority of these mutations. This is the case of more than 40 mutations that are located at exon 4. Using CRISPR/Cas9 technology, we generated a collection of Lmna exon 4 mutants in mouse C2C12 myoblasts. These cell models included different types of exon 4 deletions and the presence of R249W mutation, one of the human variants associated with a severe type of laminopathy, LMNA-associated congenital muscular dystrophy (L-CMD). We characterized these clones by measuring their nuclear circularity, myogenic differentiation capacity in 2D and 3D conditions, DNA damage, and levels of p-ERK and p-AKT (phosphorylated Mitogen-Activated Protein Kinase 1/3 and AKT serine/threonine kinase 1). Our results indicated that Lmna exon 4 mutants showed abnormal nuclear morphology. In addition, levels and/or subcellular localization of different members of the lamin and LINC (LInker of Nucleoskeleton and Cytoskeleton) complex were altered in all these mutants. Whereas no significant differences were observed for ERK and AKT activities, the accumulation of DNA damage was associated to the Lmna p.R249W mutant myoblasts. Finally, significant myogenic differentiation defects were detected in the Lmna exon 4 mutants. These results have key implications in the development of future therapeutic strategies for the treatment of laminopathies. Ministerio de Ciencia e Innovación (Acción estratégica en Salud intramural PI16III/00017-TPY1348/16). Fundación Andrés Marcio, niños contra la laminopatía (TPY-259/19). 6.600 JCR (2020) Q2, 53/195 Cell Biology 1.220 SJR (2020) Q1, 51/254 Biochemistry, Genetics and Molecular Biology (miscellaneous) No data IDR 2020 UEM
Databáze:	OpenAIRE
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