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Rev Neurosci. 2010;21(1):19-28.

CCUG repeats reduce the rate of global protein synthesis in myotonic dystrophy type 2.

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Department of Neurology, St. Josef Hospital, Ruhr-University of Bochum, Gudrunstr. 56, 44791 Bochum, Germany.


Expansion of non-coding CTG and CCTG repeats in the 3' UTR of the myotonin protein kinase (DMPK) gene in Myotonic Dystrophy type 1 (DM1) and in the intron 1 of Zinc Finger Protein 9 (ZNF9) in Myotonic Dystrophy type 2 (DM2) represent typical non-coding mutations that cause the diseases mainly through transdominant effect on the RNA metabolism (splicing, translation and RNA stability). The commonly recognized RNA gain-of-function mechanism of DM1 and DM2 suggests that the mutant CUG and CCUG RNAs play a critical role in myotonic dystrophies (DMs) without a significant role of DMPK and ZNF9. Recent studies have shown that the molecular pathogenesis of DM2 also involves the protein product of the ZNF9 gene. CCUG repeats reduce ZNF9 protein, a translational regulator of the terminal oligo-pyrimidine tract (TOP) mRNAs encoding proteins of translational apparatus. Thus, in DM2 cells, expansion of CCUG repeats affects not only multiple RNAs, but also down-regulates ZNF9 which in turn reduces translation of the TOP-containing mRNAs and diminishes the rate of global protein synthesis. In this review, we discuss the role of expansion of CCUG repeats in the reduction of ZNF9-mediated regulation of the rate of protein synthesis in DM2 and the consequences of this reduction in the multi-systemic phenotype of DM2.

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