title: Opposite phenotypes of muscle strength and locomotor function in mouse models of partial trisomy and monosomy 21 for the proximal Hspa13-App region.
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.
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors: Véronique
authors: V
authors: Brault
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors: Arnaud
authors: A
authors: Duchon
authors: LEHNA, CNRS UMR502, Université de Lyon, Villeurbanne, France.
authors: Caroline
authors: C
authors: Romestaing
authors: Genes and Disease Program, Center for Genomic Regulation, Barcelona, Spain, and CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors: Ignasi
authors: I
authors: Sahun
authors: Transgenese et Archivage Animaux Modèles, TAAM, CNRS, UPS44, Orléans, France.
authors: Stéphanie
authors: S
authors: Pothion
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors: Mona
authors: M
authors: Karout
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors: Christelle
authors: C
authors: Borel
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors: Doulaye
authors: D
authors: Dembele
authors: Key-Obs S.A., Allée du Titane, Orléans, France.
authors: Jean-Charles
authors: JC
authors: Bizot
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France.
authors: Nadia
authors: N
authors: Messaddeq
authors: Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, United States of America.
authors: Andrew J
authors: AJ
authors: Sharp
authors: LEHNA, CNRS UMR502, Université de Lyon, Villeurbanne, France.
authors: Damien
authors: D
authors: Roussel
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, Geneva, Switzerland.
authors: Stylianos E
authors: SE
authors: Antonarakis
authors: Genes and Disease Program, Center for Genomic Regulation, Barcelona, Spain, and CIBER de Enfermedades Raras (CIBERER), Barcelona, Spain.
authors: Mara
authors: M
authors: Dierssen
authors: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France; Université de Strasbourg, Illkirch, France; Institut Clinique de la Souris, PHENOMIN, GIE CERBM, Illkirch, France.
authors: Yann
authors: Y
authors: Hérault
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000503:physiopathology; D004734:Energy Metabolism / Q000235:genetics; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics; D006801:Humans; D051379:Mice; D008931:Mitochondria, Muscle / Q000235:genetics / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics; D009006:Monosomy / Q000235:genetics* / Q000503:physiopathology; D009043:Motor Activity / Q000235:genetics*; D053580:Muscle Strength / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics; D000078723:Nuclear Receptor Interacting Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051268:GA-Binding Protein Transcription Factor; C495656:Gabpa protein, mouse; C000627128:Nrip1 protein, mouse; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; C530489:ATP5b protein, mouse; D025261:Mitochondrial Proton-Translocating ATPases