The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy

Spinal muscular atrophy (SMA), which is characterized by degeneration of spinal cord lower motor neurons that leads to proximal muscle wasting and paralysis, is a common autosomal recessive disease affecting 1 in 6000 live births (Pearn, 1978; Lefebvre et al., 1995). The disease is classified into four types (Type I-IV) based on the age of onset and clinical symptoms. Although there is a wide spectrum of clinical severity, in its commonest and most severe form (Type I), SMA leads to death in infancy from respiratory muscle weakness. Even patients with non-fatal forms of SMA (Types III and IV) are considerably disabled and there is an urgent need for treatments that slow or arrest progression of the disease. The complex molecular genetic basis of SMA raises challenges for modeling the disease in other species. Owing to an intrachromosomal duplication event on chromosome 5q13, humans possess two copies of the gene encoding ‘survival motor neuron’ (SMN) – SMN1 and SMN2 (Lefebvre et al., 1995). Deletion or gene conversion events render SMA patients homozygously null for SMN1, whereas they retain a variable number of SMN2 copies. A critical C-to-T transition six base pairs into exon 7, present in all copies of the SMN2 gene described in humans to date, causes aberrant splicing of 80-90% of SMN2 transcripts, causing them to lack exon 7 (SMN7) and therefore produce a protein product with reduced stability (Lorson et al., 1999; Monani et al., 1999; Lorson and Androphy, 2000). SMN levels generally correlate with disease severity (Coovert et al., 1997; Lefebvre et al., 1997) and, because complete loss of SMN is lethal, SMA only arises as a disease in humans owing to the presence of SMN2, which provides sufficient residual full-length protein for cellular viability (McAndrew et al., 1997; Feldkötter et al., 2002; Mailman et al., 2002). SMA is therefore a disease of low levels of protein and not total ablation, a situation that any model system, either in vitro or in vivo, must reproduce in order to provide meaningful insights. SMN is widely and constitutively expressed, and has been implicated in a range of cellular processes, of which small nuclear ribonucleoprotein (snRNP) assembly is currently the best characterized (Fischer et al., 1997; Liu et al., 1997; Meister et al., 2001; Pellizzoni et al., 2002). Owing to the high degree of evolutionary conservation of the gene encoding SMN, the effects of SMN protein depletion have been modeled in diverse organisms, including in the invertebrates Caenorhabditis elegans (Briese et al., 2009; Sleigh et al., 2011) and Drosophila melanogaster (Chan et al., 2003; Chang et al., 2008), and the vertebrates Danio rerio (McWhorter et al., 2003; Boon et al., 2009) and Mus musculus (Hsieh-Li et al., 2000; Monani et al., 2000; Le et al., 2005). Zebrafish and the invertebrate models are well suited to large-scale screening PERSPECTIVE