Make sure you have at minimum watched the WK11 Concepts in Context videos on Spinal Muscular Atrophy.
Spinal Muscular Atrophy: “Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes” (2018) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026014/
Abstract:
“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 Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 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 SMN2 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 SMN exon 7 splicing. There is evidence to support that multiple exons of SMN 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 SMN genes.”
- Draw the SMN2 pre-mRNA (SMN2 has 10 exons and 9 introns), indicate the 5’ and 3’ SS location. [2pts]
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