Effect of genetic background on the phenotype of the Smn2B/- mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is caused by mutations or deletions in the Survival Motor Neuron 1 (SMN1) gene in humans. Modifiers of the SMA symptoms have been identified and genetic background has a substantial effect in the phenotype and survival of the severe mouse model of SMA. Previously, we generated the less severe Smn(2B/-) mice on a mixed genetic background. To assess the phenotype of Smn deficiency on a pure genetic background, we produced Smn(2B/2B) congenic mice on either the C57BL/6 (BL6) or FVB strain background and characterized them at the 6(th) generation by breeding to Smn(+/-)mice.Smn(2B/-) mice from these crosses were evaluated for growth, survival, muscle atrophy, motor neuron loss, motor behaviour, and neuromuscular junction pathology. FVB Smn(2B/-) mice had a shorter life span than BL6 Smn(2B/-) mice (median of 19 days vs. 25 days). Similarly, all other defects assessed occurred at earlier stages in FVB Smn(2B/-) mice when compared to BL6 Smn(2B/-) mice. However, there were no differences in Smn protein levels in the spinal cords of these mice. Interestingly, levels of Plastin 3, a putative modifier of SMA, were significantly induced in spinal cords of BL6 Smn(2B/-) mice but not of FVB Smn(2B/-)mice. Our studies demonstrate that the phenotype in Smn(2B/-) mice is more severe in the FVB background than in the BL6 background, which could potentially be explained by the differential induction of genetic modifiers.