Human Molecular Genetics, 2001, Vol. 10, No. 24 2841-2849
© 2001 Oxford University Press
Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients
1Department of Molecular and Cellular Biochemistry, 2Department of Neurology College of Medicine and 3Department of Molecular Genetics College of Biological Sciences, Ohio State University, Columbus, OH 43210, USA, 4Aurora Biosciences Corporation, 11010 Torreyana Road, San Diego, CA 92121, USA and 5Department of Dermatology, New England Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA
Proximal spinal muscular atrophy (SMA) is a common motor neuron disorder caused by mutation of the telomeric survival of motor neuron gene SMN1. The centromeric survival of motor neuron SMN2 gene is retained in all SMA patients but does not produce sufficient SMN protein to prevent the development of clinical symptoms. The SMN1 and SMN2 genes differ functionally by a single nucleotide change. This change affects the efficiency with which exon 7 is incorporated into the mRNA transcript. Thus, SMN2 produces less full-length mRNA and protein than SMN1. We have screened a library of compounds in order to identify ones that can alter the splicing pattern of the SMN2 gene. Here, we report that the compound aclarubicin increases the retention of exon 7 into the SMN2 transcript. We show that aclarubicin effectively induces incorporation of exon 7 into SMN2 transcripts from the endogenous gene in type I SMA fibroblasts as well as into transcripts from a SMN2 minigene in the motor neuron cell line NSC34. In type I fibroblasts, treatment resulted in an increase in SMN protein and gems to normal levels. Our results suggest that alteration of splicing pattern represents a new approach to modification of gene expression in disease treatment and demonstrate the feasibility of high throughput screens to detect compounds that affect the splicing pattern of a gene.
+ To whom correspondence should be addressed at: Department of Molecular and Cellular Biochemistry, Room 363 Hamilton Hall, Ohio State University, 1645 Neil Avenue, Columbus, OH 43210, USA. Tel: +1 614 688 4759; Fax: +1 614 292 4118; Email: burghes.1@osu.edu
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