Journal Article

Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients

Catia Andreassi, Jill Jarecki, Jianhua Zhou, Daniel D. Coovert, Umrao R. Monani, Xiaocum Chen, Mike Whitney, Brian Pollok, Minlei Zhang, Elliot Androphy and Arthur H.M. Burghes

in Human Molecular Genetics

Volume 10, issue 24, pages 2841-2849
Published in print November 2001 | ISSN: 0964-6906
Published online November 2001 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/10.24.2841
Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients

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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.

Journal Article.  7352 words.  Illustrated.

Subjects: Genetics and Genomics

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