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Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts

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Abstract

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA is caused by the homozygous absence of survival motor neuron-1 (SMN1). SMN2, a nearly identical copy gene, is retained in all SMA patients and encodes an identical protein as SMN1; however, SMN1 and SMN2 differ by a silent C to T transition which results in the production of an alternatively spliced isoform (SMNΔ7), which encodes a defective protein, demonstrating that the absence of the short peptide encoded by SMN exon 7 is critical in SMA development. Previously, we have shown that for some functions heterologous sequences can compensate for the exon 7 peptide, suggesting that the SMN C-terminus functions non-specifically. Consistent with this hypothesis, we now identify novel aminoglycosides that can induce SMN protein levels in patient fibroblasts. This hypothesis was supported, in part, by a novel fluorescent SMN read-through assay. Interestingly, however, through the development of a SMN exon 7-specific antibody, results suggested that levels of normal full-length SMN might also be elevated by aminoglycoside treatment. These results demonstrate that the compounds that promote read-through may provide an alternative platform for the discovery of compounds that induce SMN protein levels.

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Acknowledgments

V.B.M is supported by the Clinical BioDectives Program (NIH T90 DK070105). This work was funded by grants from FightSMA/Andrew’s Buddies (C.L.L.), the Muscular Dystrophy Association (C.L.L.) and the National Institutes of Health (C.L.L, R01 NS41584).

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Authors and Affiliations

  1. Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO, 65211-7310, USA

    Virginia B. Mattis, Tristan Coady & Christian L. Lorson

  2. Chemistry and Biochemistry, Utah State University, Logan, UT, 84322, USA

    Ravi Rai, Jinhua Wang & Cheng-Wei T. Chang

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  1. Virginia B. Mattis
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  2. Ravi Rai
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  3. Jinhua Wang
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  6. Christian L. Lorson
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Correspondence to Christian L. Lorson.

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Mattis, V.B., Rai, R., Wang, J. et al. Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts. Hum Genet 120, 589–601 (2006). https://doi.org/10.1007/s00439-006-0245-7

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