Journal Article

<i>In vitro</i> and <i>in vivo</i> suppression of <i>GJB2</i> expression by RNA interference

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

in Human Molecular Genetics

Volume 14, issue 12, pages 1641-1650
Published in print June 2005 | ISSN: 0964-6906
Published online April 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi172
In vitro and in vivo suppression of GJB2 expression by RNA interference

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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 the expression of the R75W allele variant of GJB2 in cultured mammalian cells. In a mouse model, this siRNA duplex selectively suppressed GJB2R75W expression by >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.

Journal Article.  6451 words.  Illustrated.

Subjects: Genetics and Genomics

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