title: The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy.
abstract: Proximal spinal muscular atrophy (SMA) is a common motor neuron disease in humans and in its most severe form causes death by the age of 2 years. It is caused by defects in the telomeric survival motor neuron gene ( SMN1 ), but patients retain at least one copy of a highly homologous gene, centromeric SMN ( SMN2 ). Mice possess only one survival motor neuron gene ( Smn ) whose loss is embryonic lethal. Therefore, to obtain a mouse model of SMA we created transgenic mice that express human SMN2 and mated these onto the null Smn (-/-)background. We show that Smn (-/-); SMN2 mice carrying one or two copies of the transgene have normal numbers of motor neurons at birth, but vastly reduced numbers by postnatal day 5, and subsequently die. This closely resembles a severe type I SMA phenotype in humans and is the first report of an animal model of the disease. Eight copies of the transgene rescues this phenotype in the mice indicating that phenotypic severity can be modulated by SMN2 copy number. These results show that SMA is caused by insufficient SMN production by the SMN2 gene and that increased expression of the SMN2 gene may provide a strategy for treating SMA patients.
authors.affiliation: Departments of Neurology, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
authors.forename: U R
authors.initials: UR
authors.lastname: Monani
authors.forename: M
authors.initials: M
authors.lastname: Sendtner
authors.forename: D D
authors.initials: DD
authors.lastname: Coovert
authors.forename: D W
authors.initials: DW
authors.lastname: Parsons
authors.forename: C
authors.initials: C
authors.lastname: Andreassi
authors.forename: T T
authors.initials: TT
authors.lastname: Le
authors.forename: S
authors.initials: S
authors.lastname: Jablonka
authors.forename: B
authors.initials: B
authors.lastname: Schrank
authors.forename: W
authors.initials: W
authors.lastname: Rossoll
authors.forename: W
authors.initials: W
authors.lastname: Rossol
authors.forename: T W
authors.initials: TW
authors.lastname: Prior
authors.forename: G E
authors.initials: GE
authors.lastname: Morris
authors.forename: A H
authors.initials: AH
authors.lastname: Burghes
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D015153:Blotting, Western; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D002503:Centromere; D017362:Cyclic AMP Response Element-Binding Protein; D004195:Disease Models, Animal; D005091:Exons; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D009046:Motor Neurons / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein