A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy

Abstract

5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.

Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

“…Necrosis. Similar to other milder models of SMA (13,25) and to severe models of SMA that have been therapeutically "rescued" (6,11,26), Burgheron mice develop necrosis in their tail, leading to complete tail loss by PND 45 (Fig. 1E).…”

Spinal Muscular Atrophy: Journeying From Bench to Bedside

“…Expectedly, SMN levels in 8-copy SMN2 Smn -/-mice were restored to near normal. In the years since this early work was reported, the strategy of exploiting the human SMN2 gene has been modified in subtle ways to generate a number of additional SMA model mice [62][63][64][65][66]. Their use, as described below, has not only led to novel insights into the cellular and molecular basis of the human disease, but has also served as a springboard for the design and development of promising therapies for the patient population.…”

Modeling Spinal Muscular Atrophy in Mouse: A Disease of Splicing, Stability, and Timing

“…The transgenic A2G mouse develops mild SMA early in life, though survival is near 1 year and the mice with SMA pathology can appear normal until disease progression late in life. The A2G mice are associated with motor neuron defects such as motor neuron loss, branching, neurofilament accumulation, and failure to respond to repeated stimuli (Monani et al 2003;Kariya et al 2008). The milder SMA phenotype may be explained by the partial ability of the A2G mutant SMN protein to bind to normal full-length SMN.…”

“…The milder SMA phenotype may be explained by the partial ability of the A2G mutant SMN protein to bind to normal full-length SMN. This binding is greater than that of the SMN∆7 protein, arguing the potential for partial rescue of SMN complex formation in the A2G SMA mouse model (Monani et al 2003). SMA mouse models that carry the SMN2 gene can be used to evaluate the expression and splicing of SMN2 in tissues otherwise inaccessible in SMA patients, such as the central nervous system (CNS).…”