Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

Abstract

<p>Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of <em>Survival Motor Neuron 1</em> (<em>SMN1</em>) gene. <em>SMN2</em>, a nearly identical copy of <em>SMN1</em>, does not compensate for the loss of <em>SMN1</em>due to predominant skipping of exon 7. However, correction of <em>SMN2</em> exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects <em>SMN2</em> exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7. ISS-N1 is a complex regulatory element encompassing overlapping negative motifs and sequestering a cryptic splice site. More than 40 protein factors have been implicated in the regulation of <em>SMN</em> exon 7 splicing. There is evidence to support that multiple exons of <em>SMN</em> are alternatively spliced during oxidative stress, which is associated with a growing number of pathological conditions. Here, we provide the most up to date account of the mechanism of splicing regulation of the <em>SMN</em> genes.</p>