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Human Molecular Genetics Advance Access published online on April 27, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi172
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received February 27, 2005
Revised April 12, 2005
Accepted April 22, 2005

Article

In vitro and in vivo suppression of GJB2 expression by RNA interference

Yukihide Maeda 1, Kunihiro Fukushima 2, Kazunori Nishizaki 2, and Richard J.H. Smith 1*

1 Molecular Otolaryngology Research Laboratory, Department of Otolaryngology - Head & Neck Surgery, Interdepartmental PhD Genetics Program, The University of Iowa, Iowa City, IA 52242, USA
2 Department of Otolaryngology - Head and Neck Surgery, Okayama University Graduate School of Medicine, Okayama, Okayama 700-8558, Japan

* To whom correspondence should be addressed.
Richard J.H. Smith, E-mail: richard-smith{at}uiowa.edu


  Abstract

Mutations in GJB2 (gap junction protein, beta-2) are the major cause of autosomal recessive non-syndromic hearing loss. A few allele variants of this gene also cause autosomal dominant non-syndromic hearing loss as a dominant-negative consequence of expression of the mutant protein. Allele-specific gene suppression by RNA interference (RNAi) is a potentially attractive strategy to prevent hearing loss caused by this mechanism. In this proof-of-principle study, we identified a potent GJB2-targeting short interfering RNA (siRNA) to post-transcriptionally silence expression of the R75W allele variant of GJB2 in cultured mammalian cells. In a mouse model, this siRNA duplex selectively suppressed GJB2R75W expression by more than 70% of control levels thereby preventing hearing loss. The level of endogenous murine Gjb2 expression was not affected. Our data show that RNAi can be used with specificity and efficiency in vivo to protect against hearing loss caused as a dominant-negative consequence of mutant gene expression.


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