Human Genetics

, Volume 120, Issue 4, pp 589–601

Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts

  • Virginia B. Mattis
  • Ravi Rai
  • Jinhua Wang
  • Cheng-Wei T. Chang
  • Tristan Coady
  • Christian L. Lorson
Original Investigation

DOI: 10.1007/s00439-006-0245-7

Cite this article as:
Mattis, V.B., Rai, R., Wang, J. et al. Hum Genet (2006) 120: 589. doi:10.1007/s00439-006-0245-7

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.

Supplementary material

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Virginia B. Mattis
    • 1
  • Ravi Rai
    • 2
  • Jinhua Wang
    • 2
  • Cheng-Wei T. Chang
    • 2
  • Tristan Coady
    • 1
  • Christian L. Lorson
    • 1
  1. 1.Department of Veterinary Pathobiology, Life Sciences CenterUniversity of MissouriColumbiaUSA
  2. 2.Chemistry and BiochemistryUtah State UniversityLoganUSA