Molecular Parallels with Myotonic Dystrophy

Similar to SCA8, DM1 is also caused by a d(CTG) repeat expansion that is transcribed but not translated (Tapscott 2000). In 1992, the DM1 mutation was identified as a d(CTG) expansion in the 3' untranslated region of the DMPK gene; however, the molecular mechanism underlying the pathogenesis of this expansion was not clear. In 2001, we identified the mutation that causes DM2, which is characterized by the same multisystemic features as DM1, but results from a noncoding r(CCUG) expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene (Liquori et al. 2001). The DMPK and ZNF9 genes and the surrounding regions bear no obvious similarity, but the fact that both mutations involve similar expanded repeat motifs that are transcribed but untranslated pointed to an RNA gain-of-function mechanism. The identification of the DM2 mutation and experiments demonstrating ribonuclear foci formation and downstream alternative splicing of other genes have established that the clinical features common to DM1 and DM2 are caused by an RNA gain-of-function mechanism. Molecular parallels between SCA8, DM1, and DM2 mutations, along with the known toxic properties of transcripts containing expanded r(CUG) repeats, suggest the possibility that a similar mechanism may play a role in SCA8 pathogenesis (Mosemiller et al. 2003). The SCA8 gene is almost exclusively expressed in the CNS but the DMPK and ZNF9 genes are broadly expressed, consistent with the differing clinical features of the diseases (Koob et al. 1999; Liquori et al. 2001).

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