Identification of a phenotype caused by perturbed miRNA-mediated gene regulation

In 2006, we discovered that the muscular hypertrophy that is typical of Texel sheep is due – at least in part - to a point mutation in the 3’UTR of the myostatin (MSTN) gene that creates an illegitimate target site for miR-1 and miR-202, two miRNAs that are highly expressed in skeletal muscle.  These miRNAs inhibit the translation of the corresponding mRNAs without significantly affecting their concentrations.  This is the first and still amongst the most convincing examples of a mammalian phenotype (including humans) that is due to perturbed miRNA-mediated gene regulation.  Based on these results, we developed a database of genetic variants in human and other organisms that are potentially affecting miRNA mediated gene regulation, as well as an experimental method based on AGO-IP to demonstrate polymorphic miRNA-mediated gene regulation in vivo.  

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Key publications

Demonstrating polymorphic miRNA-mediated gene regulation in vivo: application to the g+6223G->A mutation of Texel sheep. Takeda H, Charlier C, Farnir F, Georges M. RNA 16:1854-1863 (2010).

Patrocles: a database of polymorphic miRNA-mediated gene regulation in vertebrates. Hiard S, Charlier C, Coppieters W, Georges M, Baurain D. Nucleic Acids Res 38(Database issue):D640-51 (2010).

Polymorphic miRNA-mediated gene regulation: contribution to phenotypic variation and disease. Georges M, Coppieters W, Charlier C. Curr Opin Genet Dev 17:166-176 (2007).

A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep. Clop A, Marcq F, Takeda H, Pirottin D, Tordoir X, Bibé B, Bouix J, Caiment F, Elsen JM, Eychenne F, Larzul C, Laville E, Meish F, Milenkovic D, Tobin J, Charlier C, Georges M. Nat Genet 38:813-818 (2006).

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