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A spanner in the works of human transformer 2 β1 autoregulation may reduce the severity of spinal muscular atrophy

Pitout, I., Fletcher, S., Etherington, S.ORCID: 0000-0002-6589-8793 and Wilton, S. (2015) A spanner in the works of human transformer 2 β1 autoregulation may reduce the severity of spinal muscular atrophy. The Journal of Gene Medicine, 17 (8 - 9). pp. 173-217.

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Modifier genes involved in pre‐mRNA splicing have potential as novel therapeutic targets for reducing the severity of genetic diseases. Spinal muscular atrophy (SMA), is a devastating neurodegenerative disease caused by homozygous loss of the survival motor neuron 1 (SMN1) gene. The absence of SMN is embryonic lethal but humans have one or more near‐identical copies of SMN2 that provide low levels of full length SMN (FL‐SMN). A single nucleotide change in SMN2 exon 7 creates a splice‐silencer and leads to the predominant production of ∆7‐SMN. Human transformer protein 2 beta 1 (TRA2β1), binds a splice‐enhancer element in SMN exon 7, contributing to the production of FL‐SMN. Studies show that increasing TRA2β1 concentration in vitro leads to 80% of the SMN2 transcripts being FL. We upregulated TRA2β1 by interrupting its autoregulation mechanism with antisense oligonucleotides (AOs). When TRA2B1 is in molar excess it binds to splice‐enhancer motifs in exon 2 of the TRA2β pre‐mRNA, causing an increase in nonfunctional alternative transcripts containing exon 2 and a concurrent decrease in the TRA2β1 transcript. We transfected SMA patient fibroblasts with 2'O‐methyl AOs targeting exon 2 of TRA2β to interfere with TRA2β1 autoregulation. Fibroblasts were harvested at various time points for transcript analysis. Quantitative polymerase chain reaction (PCR) of the TRA2β transcripts showed a decrease in the alternative transcripts and an increase in TRA2β1 transcripts. Reverse transcriptase‐PCR showed an corresponding increase in FL‐SMN. TRA2β1 corrects the splicing of SMN2 to produce more FL‐SMN; therefore, up‐regulating it may be a useful complementary approach in developing a therapy for SMA.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Comparative Genomics
School of Veterinary and Life Sciences
Publisher: Wiley
Copyright: © 2015 John Wiley & Sons, Ltd.
Other Information: Poster presentation given @ Ninth Australasian Gene and Cell Therapy Society Meeting, The University of Melbourne, Parkville, VIC 29 April - 1 May 2015
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