DM is genetically heterogeneous and comprises at least two disorders (DM1 and DM2). DM1 and DM2 are clinically similar, progressive multisystem, myotonic disorders due to a CTG repeat expansion in the DMPK gene (DM1) or to a CCTG repeat expansion in the ZNF9 gene (DM2). Both expansions show high somatic, interindividual, and intergenerational instability and uncertain genotype-phenotype correlation. Both expansions are transcribed but not translated. Transcripts of the mutant alleles, harboring large CUG and CCUG expansions, are retained within nuclear foci. Suggested pathomechanism is considered to be a transdominant effect on the function of RNA-binding proteins, rather than haploinsufficiency. CUG-binding proteins regulate alternative splicing of proteins such as troponine-T, insulin receptor, ClC-1, myotubularin-1, tau protein, myo-D, and presumably various other mRNAs. Genetic counseling is hampered by the high expansion variability. Therapy of DM1 and DM2 is symptomatic. Preliminary results show that ribozyme-mediated cleavage of mutant DMPK mRNA reduces nuclear foci and partially restores function of the insulin receptor. Other promising therapeutic concepts rely on the delivery of antisense RNA, which is capable of inhibiting mutant DMPK transcripts. Paralleles between the ZNF9 gene mutation and the DMPK gene mutation indicate that RNA microsatellite expansions in a noncoding portion of a gene, transcribed but untranslated, are pathogenic and cause multisystem disease.
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