Regulation of SMN2 splicing in cell and mouse models of Spinal Muscular Atrophy

Most human genes contain introns that need to be excised from the mRNA before its translation through a process named splicing. The regulation of splicing is orchestrated by numerous proteins, RNAs and sequence elements located in the introns and exons of the gene that compose the so called splicing code. A large number of disease-causing genetic mutations are known to affect the splicing code without altering the open reading frames of the proteins encoded by the gene. One of the best characterized genetic diseases caused by aberrant splicing regulation is Spinal Muscular Atrophy (SMA), an autosomal recessive neuromuscular disorder representing the primary genetic cause of infant mortality. SMA is caused by inactivating mutations in SMN1, which encodes the Survival of Motor Neuron protein (SMN). Although SMA patients retain the almost identical SMN2 gene, a single nucleotide change in SMN2 causes the exclusion of exon 7 from the mature mRNA and the production of an unstable protein. Hence, regulation of exon 7 splicing in the SMN2 mRNA represents a valuable therapeutic approach for the correction of this disease−causing genetic defect in SMA patients. We have identified the first splicing factor that modulates SMN2 splicing in a SMA mouse model, thus affecting the phenotype. Moreover, we found additional splicing factors involved in the mechanism of action of drugs currently in trials for SMA. Thus, the studies proposed in this project are relevant for the comprehension of the molecular mechanism(s) involved in the defect causing SMA, a well-described example of inheritable disease of known genetic cause, and might hold promise for future applications as therapeutic approaches to SMA. Furthermore, since defects in splicing are likely to affect other neurodegenerative diseases whose cause remains unknown, our studies might provide a useful model also for the study of such diseases.