The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy

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 i s 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 l oss is embryonic lethal. Therefore, to obtain a mouse model of SMA we creat ed transgenic mice that express human SMN2 and mated these onto the null Sm m(-/-) background. We show that Smn(-/-);SMN2 mice carrying one or two copi es of the transgene have normal numbers of motor neurons at birth, but vast ly reduced numbers by postnatal day 5, and subsequently die. This closely r esembles 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.