Human Molecular Genetics Advance Access originally published online on November 13, 2008
Human Molecular Genetics 2009 18(3):546-555; doi:10.1093/hmg/ddn382
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Rescue of a severe mouse model for spinal muscular atrophy by U7 snRNA-mediated splicing modulation
,1 Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland 2 Laboratory of Virology and Genetics, School of Life Sciences, EPFL Lausanne, Switzerland
* To whom correspondence should be addressed. Tel: +41 31 631 4675; Fax: +41 31 631 4616; Email: daniel.schuemperli{at}izb.unibe.ch
Received October 9, 2008; Accepted November 10, 2008
In spinal muscular atrophy (SMA), the leading genetic cause of early childhood death, the survival motor neuron 1 gene (SMN1) is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilization of exon 7 and the production of functional protein. It has been hypothesized that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evidence for an in vivo improvement of SMA symptoms is lacking. Here, we unambiguously confirm the above hypothesis by showing that a bifunctional U7 snRNA that stimulates exon 7 inclusion, when introduced by germline transgenesis, can efficiently complement the most severe mouse SMA model. These results are significant for the development of a somatic SMA therapy, but may also provide new means to study pathophysiological aspects of this devastating disease.
Present address: Laboratory of Virology and Genetics, School of Life Sciences, EPFL Lausanne, Switzerland.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.