Chapter title |
Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes
|
---|---|
Chapter number | 2 |
Book title |
RNA Metabolism in Neurodegenerative Diseases
|
Published in |
Advances in neurobiology, January 2018
|
DOI | 10.1007/978-3-319-89689-2_2 |
Pubmed ID | |
Book ISBNs |
978-3-31-989688-5, 978-3-31-989689-2
|
Authors |
Ravindra N. Singh, Natalia N. Singh, Singh, Ravindra N., Singh, Natalia N. |
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. |
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