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Human Molecular Genetics Advance Access originally published online on August 19, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 20 2637-2644
DOI: 10.1093/hmg/ddg280
© 2003 Oxford University Press

Allele-specific silencing of a pathogenic mutant acetylcholine receptor subunit by RNA interference

Amr Abdelgany1, Matthew Wood2 and David Beeson1,*

1Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK and 2Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK

Received June 6, 2003; Revised July 18, 2003; Accepted August 11, 2003

Slow channel congenital myasthenic syndrome (SCCMS) is a disorder of the neuromuscular synapse caused by dominantly inherited missense mutations in genes that encode the muscle acetylcholine receptor (AChR) subunits. Here we investigate the potential of post-transcriptional gene silencing using RNA interference (RNAi) for the selective down-regulation of pathogenic mutant AChR. By transfection of both siRNA and shRNA into mammalian cells expressing wild-type or mutant AChR subunits, we show, using 125I-{alpha}-bungarotoxin binding and immunofluorescence to measure cell surface AChR expression, efficient discrimination between the silencing of {alpha}S226F AChR mutant RNA transcripts and the wild-type. In this model we find that selectivity between mutant and wild-type transcripts is optimized with the nucleotide mismatch at position 9 in the shRNA complementary sequence. We also find that allele-specific silencing using shRNA has comparable efficiency to that using siRNA, underlining the general potential of stable expression of shRNA molecules as a long term therapeutic approach for allele-specific silencing of mutant transcripts in dominant genetic disorders.

* To whom correspondence should be addressed. Email: dbeeson{at}hammer.imm.ox.ac.uk


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