title: Neuromuscular defects and breathing disorders in a new mouse model of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein leading to muscle paralysis and respiratory failure. In mouse, introducing the human SMN2 gene partially rescues Smn(-)(/)(-) embryonic lethality. However current models were either too severe or nearly unaffected precluding convenient drug testing for SMA. We report here new SMN2;Smn(-/-) lines carrying one to four copies of the human SMN2 gene. Mice carrying three SMN2 copies exhibited an intermediate phenotype with delayed appearance of motor defects and developmental breathing disorders reminiscent of those found in severe SMA patients. Although normal at birth, at 7 days of age respiratory rate was decreased and apnea frequency was increased in SMA mice in parallel with the appearance of neuromuscular junction defects in the diaphragm. With median survival of 15 days and postnatal onset of neurodegeneration, these mice could be an important tool for evaluating new therapeutics.
authors.affiliation: Trophos, Parc Scientifique de Luminy, Luminy Biotech Entreprise, Case 931, 13288 Marseille, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Michaud
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnoux
authors.forename: Serena
authors.initials: S
authors.lastname: Bielli
authors.forename: Estelle
authors.initials: E
authors.lastname: Durand
authors.forename: Yann
authors.initials: Y
authors.lastname: Rotrou
authors.forename: Sibylle
authors.initials: S
authors.lastname: Jablonka
authors.forename: Fabrice
authors.initials: F
authors.lastname: Robert
authors.forename: Marc
authors.initials: M
authors.lastname: Giraudon-Paoli
authors.forename: Markus
authors.initials: M
authors.lastname: Riessland
authors.forename: Marie-Geneviève
authors.initials: MG
authors.lastname: Mattei
authors.forename: Emile
authors.initials: E
authors.lastname: Andriambeloson
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
authors.forename: Michael
authors.initials: M
authors.lastname: Sendtner
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallego
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Pruss
authors.forename: Thierry
authors.initials: T
authors.lastname: Bordet
mesh_terms: D000818:Animals; D003964:Diaphragm / Q000294:innervation / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005804:Genes, Lethal / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020511:Neuromuscular Junction Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012131:Respiratory Insufficiency / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012133:Respiratory Paralysis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein