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http://hdl.handle.net/2445/186222
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DC Field | Value | Language |
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dc.contributor.author | López-Márquez, Arístides | - |
dc.contributor.author | Morín, Matías | - |
dc.contributor.author | Fernández-Peñalver, Sergio | - |
dc.contributor.author | Badosa, Carmen | - |
dc.contributor.author | Hernández-Delgado, Alejandro | - |
dc.contributor.author | Natera-de Benito, Daniel | - |
dc.contributor.author | Ortez, Carlos | - |
dc.contributor.author | Nascimento, Andrés | - |
dc.contributor.author | Grinberg Vaisman, Daniel Raúl | - |
dc.contributor.author | Balcells Comas, Susana | - |
dc.contributor.author | Roldán Molina, Mònica | - |
dc.contributor.author | Moreno-Pelayo, Miguel Ángel | - |
dc.contributor.author | Jiménez-Mallebrera, Cecilia | - |
dc.date.accessioned | 2022-06-01T17:02:34Z | - |
dc.date.available | 2022-06-01T17:02:34Z | - |
dc.date.issued | 2022-04-16 | - |
dc.identifier.issn | 1661-6596 | - |
dc.identifier.uri | http://hdl.handle.net/2445/186222 | - |
dc.description.abstract | Collagen VI-related disorders are the second most common congenital muscular dystrophies for which no treatments are presently available. They are mostly caused by dominant-negative pathogenic variants in the genes encoding α chains of collagen VI, a heteromeric network forming collagen; for example, the c.877G>A; p.Gly293Arg COL6A1 variant, which alters the proper association of the tetramers to form microfibrils. We tested the potential of CRISPR/Cas9-based genome editing to silence or correct (using a donor template) a mutant allele in the dermal fibroblasts of four individuals bearing the c.877G>A pathogenic variant. Evaluation of gene-edited cells by next-generation sequencing revealed that correction of the mutant allele by homologous-directed repair occurred at a frequency lower than 1%. However, the presence of frameshift variants and others that provoked the silencing of the mutant allele were found in >40% of reads, with no effects on the wild-type allele. This was confirmed by droplet digital PCR with allele-specific probes, which revealed a reduction in the expression of the mutant allele. Finally, immunofluorescence analyses revealed a recovery in the collagen VI extracellular matrix. In summary, we demonstrate that CRISPR/Cas9 gene-edition can specifically reverse the pathogenic effects of a dominant negative variant in COL6A1. | - |
dc.format.extent | 17 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | MDPI | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.3390/ijms23084410 | - |
dc.relation.ispartof | International Journal of Molecular Sciences, 2022, vol. 23, num. 8, p. 4410 | - |
dc.relation.uri | https://doi.org/10.3390/ijms23084410 | - |
dc.rights | cc-by (c) López-Márquez, Arístides et al., 2022 | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.source | Articles publicats en revistes (Genètica, Microbiologia i Estadística) | - |
dc.subject.classification | Distròfia muscular | - |
dc.subject.classification | Mutació (Biologia) | - |
dc.subject.other | Muscular dystrophy | - |
dc.subject.other | Mutation (Biology) | - |
dc.title | CRISPR/Cas9-mediated allele-specific disruption of a dominant COL6A1 pathogenic variant improves collagen VI network in patient fibroblasts | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 722981 | - |
dc.date.updated | 2022-06-01T17:02:34Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (Genètica, Microbiologia i Estadística) |
Files in This Item:
File | Description | Size | Format | |
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722981.pdf | 4.94 MB | Adobe PDF | View/Open |
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