title: Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts.
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 (SMNDelta7), 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.
authors.affiliation: Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO 65211-7310, USA.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Mattis
authors.forename: Ravi
authors.initials: R
authors.lastname: Rai
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.forename: Cheng-Wei T
authors.initials: CW
authors.lastname: Chang
authors.forename: Tristan
authors.initials: T
authors.lastname: Coady
authors.forename: Christian L
authors.initials: CL
authors.lastname: Lorson
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D013997:Time Factors; D014162:Transfection
chemical_list: D000617:Aminoglycosides; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D049452:Green Fluorescent Proteins; D008156:Luciferases; D051548:Histone Acetyltransferases