title: Development and characterization of an SMN2-based intermediate mouse model of Spinal Muscular Atrophy.
abstract: Spinal Muscular Atrophy (SMA) is due to the loss of the survival motor neuron gene 1 (SMN1), resulting in motor neuron (MN) degeneration, muscle atrophy and loss of motor function. While SMN2 encodes a protein identical to SMN1, a single nucleotide difference in exon 7 causes most of the SMN2-derived transcripts to be alternatively spliced resulting in a truncated and unstable protein (SMNΔ7). SMA patients retain at least one SMN2 copy, making it an important target for therapeutics. Many of the existing SMA models are very severe, with animals typically living less than 2 weeks. Here, we present a novel intermediate mouse model of SMA based upon the human genomic SMN2 gene. Genetically, this model is similar to the well-characterized SMNΔ7 model; however, we have manipulated the SMNΔ7 transgene to encode a modestly more functional protein referred to as SMN read-through (SMN(RT)). By introducing the SMN(RT) transgene onto the background of a severe mouse model of SMA (SMN2(+/+);Smn(-/-)), disease severity was significantly decreased based upon a battery of phenotypic parameters, including MN pathology and a significant extension in survival. Importantly, there is not a full phenotypic correction, allowing for the examination of a broad range of therapeutics, including SMN2-dependent and SMN-independent pathways. This novel animal model serves as an important biological and therapeutic model for less severe forms of SMA and provides an in vivo validation of the SMN(RT) protein.
authors: Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
authors: Melissa S
authors: MS
authors: Cobb
authors: Ferril F
authors: FF
authors: Rose
authors: Hansjörg
authors: H
authors: Rindt
authors: Jacqueline J
authors: JJ
authors: Glascock
authors: Monir
authors: M
authors: Shababi
authors: Madeline R
authors: MR
authors: Miller
authors: Erkan Y
authors: EY
authors: Osman
authors: Pei-Fen
authors: PF
authors: Yen
authors: Michael L
authors: ML
authors: Garcia
authors: Brittanie R
authors: BR
authors: Martin
authors: Mary J
authors: MJ
authors: Wetz
authors: Chiara
authors: C
authors: Mazzasette
authors: Zhihua
authors: Z
authors: Feng
authors: Chien-Ping
authors: CP
authors: Ko
authors: Christian L
authors: CL
authors: Lorson
mesh_terms: D000818:Animals; D001835:Body Weight; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012313:RNA / Q000235:genetics; D012326:RNA Splicing; D013116:Spinal Cord / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics*
chemical_list: D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D012313:RNA