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Human Molecular Genetics Advance Access originally published online on March 24, 2005
Human Molecular Genetics 2005 14(9):1199-1210; doi:10.1093/hmg/ddi131
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

A non-sequence-specific requirement for SMN protein activity: the role of aminoglycosides in inducing elevated SMN protein levels

Elizabeth C. Wolstencroft, Virginia Mattis, Anna A. Bajer, Philip J. Young{dagger} and Christian L. Lorson*

Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65211-7310, USA

* To whom correspondence should be addressed at: Department of Veterinary Pathobiology Life Sciences Center, 471G, 1201 Rollins Road, University of Missouri, Columbia, MO 65211-7310, USA. Tel: +1 5738842219; Fax: +1 5738849395; Email: lorsonc{at}missouri.edu

Received February 1, 2005; Revised March 13, 2005; Accepted March 13, 2005

Spinal muscular atrophy (SMA) is caused by homozygous loss of the survival motor neuron (SMN1) gene. In virtually all SMA patients, a nearly identical copy gene is present, SMN2. SMN2 cannot fully compensate for the loss of SMN1 because the majority of transcripts derived from SMN2 lack a critical exon (exon 7), resulting in a dysfunctional SMN protein. Therefore, the critical distinction between a functional and a dysfunctional SMN protein is the inclusion or the exclusion of the exon 7 encoded peptide. To determine the role of the 16 amino acids encoded by SMN exon 7, a panel of synthetic mutations were transiently expressed in SMA patient fibroblasts and HeLa cells. Consistent with previous reports, the protein encoded by SMN exons 1–6 was primarily restricted to the nucleus. However, a variety of heterologous sequences fused to the C-terminus of SMN exons 1–6 allowed mutant SMN proteins to properly distribute to the cytoplasm and to the nuclear gems. These data demonstrate that the SMN exon 7 sequence is not specifically required, rather this region functions as a non-specific ‘tail’ that facilitates proper localization. Therefore, a possible means to restore additional activity to the SMN{Delta}7 protein could be to induce a longer C-terminus by suppressing recognition of the native stop codon. To address this possibility, aminoglycosides were examined for their ability to restore detectable levels of SMN protein in SMA patient fibroblasts. Aminoglycosides can suppress the accurate identification of translation termination codons in eukaryotic cells. Consistent with this, treatment of SMA patient fibroblasts with tobramycin and amikacin resulted in a quantitative increase in SMN-positive gems and an overall increase in detectable SMN protein. Taken together, this work describes the role of the critical exon 7 region and identifies a possible alternative approach for therapeutic intervention.

{dagger} Present address: Peninsula Medical School, University of Exeter, St Luke's Campus, Exeter EX1 2LU, UK.


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