Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2)

Spinal muscular atrophy (SMA), a common motor neuron disease in humans, res ults from loss of functional survival motor neuron (SMN1) alleles. A nearly identical copy of the gene, SMN2, fails to provide protection from SMA bec ause of a single translationally silent nucleotide difference in exon 7. Th is likely disrupts an exonic splicing enhancer and causes exon 7 skipping, leading to abundant production of a shorter isoform, SMN2 Delta 7. The trun cated transcript encodes a less stable protein with reduced self-oligomeriz ation activity that fails to compensate for the toss of SMN1. This report d escribes the identification of an in vivo regulator of SMN mRNA processing. Htra2-beta 1, an SR-like splicing factor and ortholog of Drosophila melano gaster transformer-2, promoted the inclusion of SMN exon 7, which would sti mulate full-length SMN2 expression. Htra2-beta 1 specifically functioned th rough and bound an AG-rich exonic splicing enhancer in SMN exon 7. This eff ect is not species-specific as expression of Htra2-beta 1: in human or mous e cells carrying an SMN2 minigene dramatically increased production of full -length SMN2. This demonstrates that SMN2 mRNA processing can be modulated in vivo. Because all SMA patients retain at least one SMN2 copy, these resu lts show that an in vivo modulation of SMN RNA processing could serve as a therapeutic strategy to prevent SMA.