RESEARCH SUPPORT, NON-U.S. GOV'T
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SMN transcript stability: could modulation of messenger RNA degradation provide a novel therapy for spinal muscular atrophy?

Proximal spinal muscular atrophy is caused by deletion or mutation of the survival motor neuron 1 gene, SMN1. Rentention of a nearly identical copy gene, SMN2, enables survival but is unable to fully compensate for the loss of SMN1. The SMN1 and SMN2 genes differ by a single nucleotide that results in alternative splicing of SMN2 exon 7 due to the disruption of a binding site for an essential splicing factor. This alternatively spliced form encodes a partially functional truncated protein. Because SMN2 is present in patients with spinal muscular atrophy, it is an ideal therapeutic target. Some of the current approaches to increase SMN protein levels are aimed at increasing the transcription from SMN2 or at preventing exon 7 skipping. One area that has yet to be investigated is the stability of messenger ribonucleic acid (RNA) transcripts produced from SMN2. We postulated that transcripts derived from SMN2 may be less stable because alternative splicing, recruitment of RNA-binding proteins, and alteration of stop codons have been associated with changes in rates of messenger RNA decay; these features are all characteristic of SMN2. Accordingly, transcript degradation was examined within primary fibroblast cells that exclusively contained SMN1 or SMN2 by treating cultures with a transcriptional inhibitor to observe messenger RNA stability. The results indicate that SMN transcript instability does not play a role in the disease mechanism, suggesting that therapeutic modulation of messenger RNA degradation would not target a molecular defect in patients with spinal muscular atrophy, although it could provide general benefits by increasing total pools of SMN2 transcripts.

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