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Opposite phenotypes of muscle strength and locomotor function in mouse models of partial trisomy and monosomy 21 for the proximal Hspa13-App region

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dc.contributor.author Brault, Véronique
dc.contributor.author Duchon, Arnaud
dc.contributor.author Romestaing, Caroline
dc.contributor.author Sahún, Ignasi
dc.contributor.author Pothion, Stéphanie
dc.contributor.author Karout, Mona
dc.contributor.author Borel, Christelle
dc.contributor.author Dembele, Doulaye
dc.contributor.author Bizot, Jean-Charles
dc.contributor.author Messaddeq, Nadia
dc.contributor.author Sharp, Andrew J.
dc.contributor.author Roussel, Damien
dc.contributor.author Antonarakis, Stylianos E.
dc.contributor.author Dierssen, Mara
dc.contributor.author Hérault, Yann
dc.date.accessioned 2015-11-19T13:11:27Z
dc.date.available 2015-11-19T13:11:27Z
dc.date.issued 2015
dc.identifier.citation Brault V, Duchon A, Romestaing C, Sahun I, Pothion S, Karout M et al. Opposite phenotypes of muscle strength and locomotor function in mouse models of partial trisomy and monosomy 21 for the proximal Hspa13-App region. PLoS genetics. 2015; 11(3): e1005062. DOI 10.1371/journal.pgen.1005062
dc.identifier.issn 1553-7390
dc.identifier.uri http://hdl.handle.net/10230/25151
dc.description.abstract The trisomy of human chromosome 21 (Hsa21), which causes Down syndrome (DS), is the most common viable human aneuploidy. In contrast to trisomy, the complete monosomy (M21) of Hsa21 is lethal, and only partial monosomy or mosaic monosomy of Hsa21 is seen. Both conditions lead to variable physiological abnormalities with constant intellectual disability, locomotor deficits, and altered muscle tone. To search for dosage-sensitive genes involved in DS and M21 phenotypes, we created two new mouse models: the Ts3Yah carrying a tandem duplication and the Ms3Yah carrying a deletion of the Hspa13-App interval syntenic with 21q11.2-q21.3. Here we report that the trisomy and the monosomy of this region alter locomotion, muscle strength, mass, and energetic balance. The expression profiling of skeletal muscles revealed global changes in the regulation of genes implicated in energetic metabolism, mitochondrial activity, and biogenesis. These genes are downregulated in Ts3Yah mice and upregulated in Ms3Yah mice. The shift in skeletal muscle metabolism correlates with a change in mitochondrial proliferation without an alteration in the respiratory function. However, the reactive oxygen species (ROS) production from mitochondrial complex I decreased in Ms3Yah mice, while the membrane permeability of Ts3Yah mitochondria slightly increased. Thus, we demonstrated how the Hspa13-App interval controls metabolic and mitochondrial phenotypes in muscles certainly as a consequence of change in dose of Gabpa, Nrip1, and Atp5j. Our results indicate that the copy number variation in the Hspa13-App region has a peripheral impact on locomotor activity by altering muscle function.
dc.description.sponsorship The project was supported by the French National Centre for Scientific Research (CNRS), the French National Institute of Health and Medical Research (INSERM), the University of Strasbourg and the “Centre Europeen de Recherche en Biomedecine”, the “Fondation Jerome Lejeune”, and the European commission (AnEUploidy project/nLSHG-CT-2006-037627 to YH, MD and SEA). The laboratory of SEA was supported by grants from The Swiss National Science Foundation (144082), the EU AnEUploidy project (LSHG-CT-2006-037627), and the ERC (249968). This study been supported by French state funds through the “Agence Nationale de la Recherche” under the frame programme Investissements d’Avenir labelled ANR-10-IDEX- 0002-02, ANR-10-LABX-0030-INRT, ANR-10-INBS-07 PHENOMIN.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Public Library of Science (PLoS)
dc.relation.ispartof PLoS genetics. 2015; 11(3): e1005062
dc.rights © 2015 Brault et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Down, Síndrome de -- Aspectes genètics
dc.title Opposite phenotypes of muscle strength and locomotor function in mouse models of partial trisomy and monosomy 21 for the proximal Hspa13-App region
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1371/journal.pgen.1005062
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/037627
dc.relation.projectID info:eu-repo/grantAgreement/EC/ERC/249968
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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