A SMNΔ7 read-through product confers functionality to the SMNΔ7 protein

Spinal muscular atrophy (SMA) affects about 1 in every 6000 children born and is the leading genetic cause of infant death. SMA is a recessive disorder caused by the mutation or deletion of Survival Motor Neuron-1 (SMN1). SMN2, a nearly identical copy gene, has the potential to encode the same protein as SMN1 and is retained in all SMA patients. The majority of SMN2-derived transcripts are alternatively spliced and therefore encode a truncated isoform lacking exon 7 (SMNΔ7), which is a defective protein because it is unstable, has a reduced ability to self-associate and is unable to efficiently function in SMN cellular activities. However, we have shown that the SMN C-terminus functions non-specifically, since heterologous sequences can compensate for the exon 7 sequence. Several classes of compounds identified in SMN-inducing high throughput screens have been proposed to function through a read-through mechanism; however, a functional analysis of the SMNΔ7 read-through product has not been performed. In this report, the SMNΔ7 read-through product is characterized and compared to the SMNΔ7 protein. In a series of in vitro and cell based assays, SMNΔ7 read-through product is shown to increase protein stability, promote neurite outgrowths in SMN deficient neurons, and significantly elevate SMN-dependent UsnRNP assembly in extracts from SMA patient fibroblasts. Collectively, these results demonstrate that SMNΔ7 read-through product is more active than the SMNΔ7 protein and suggest that SMA therapeutics that specifically induce SMNΔ7 read-through may provide an alternative platform for drug discovery.