fig9

Figure 9. Summary of the genetic and molecular defects causing the several types of SMA severity and of treatment by a blocker ASO. A: In non-affected individuals, both SMN1 and SMN2 genes are functional wild-type. SMN1 pre-mRNA is transcribed into a complete mRNA corresponding to the 9 exons: 1,2a,2B,3,4,5, 6,7and 8. This leads to the production of a completely functional SMN1 protein, which does not occur in SMA patients. B: The SMN2 paralog gene contains several sequences which negatively impact the correct splicing and impair the incorporation of Exon 7 into the maturated SMN2 mRNA. The most important of these inhibitory sequences is the intronic splicing silencer N1 (ISS N1) located in 5’ of Intron 7. Therefore, only a 10 to 20 % minority of SMN2 transcripts contain all necessary exonic sequences for a functional SMN2 protein. From 80 to 90% of SMN2 transcripts are translated in a shortened non-functional SMN2 protein devoid of Exon 7, which is unstable. The presence of multiple copies of the SMN2 gene results in a higher quantity of functional SMN2 being produced and partially alleviates the disease severity. Type I patients generally possess 2 SMN2 copies, Type II having 3 SMN2 copies, and Type III and IV having 4 SMN2 gene copies. C: In SMA patients, a mutation/deletion induces the loss of SMN1 protein production. An ASO designed as a steric blocker of ISS N1 is highly efficient in increasing the level of fully competent SMN2 protein, and has been clinically validated as the Nusinersen drug.