We demonstrated previously that myotonic dystrophy type 2 (DM2) is caused by a CCTG expansion in intron 1 of the ZA/F9gene. Parallels between the DM1 and DM2 expansion mutations and the characterization of RNA binding proteins that interact with expanded CUG and CCUG repeats have uncovered a novel type of mechanism involving RNA gain-of-function effects. In this model, the accumulation of CUG or CCUG expansion transcripts results in the dysregulation of RNA binding proteins normally involved in controlling developmental changes in alternative splicing of a specific set of pre-mRNA transcripts. The failure of this set of normal developmental splicing changes is thought to occur, at least in part, because the accumulation of CUG and CCUG expansion transcripts in DM1 and DM2 leads to sequestration and depletion of nuclear MBNL1. Remarkably, recent studies performed by Dr. Swanson's group now show that AAV injection of constructs overexpressing Mbnll can rescue the muscle phenotype and reverse the splicing alterations in a skeletal muscle poly(CUG) model of DM1. Although significant progress has been made in understanding the pathology and the molecular mechanisms of RNA pathogenesis in skeletal and cardiac muscle, little is known about the molecular changes underlying a clinically important, but poorly understood, set of CNS effects in DM1 and DM2. Patients with adult onset DM1 and DM2 have strikingly similar multisystemic diseases, with preliminary data suggesting similar cerebral and cerebellar white matter abnormalities as well as executive function deficits. Congenially affected DM1 patients have more severe CNS abnormalities including mental retardation. A possible mechanism for congenital DM1 is that methylation at the DM1 locus in congenital cases is associated with increased expression of DMPK, resulting in higher levels of CUG containing transcripts and a more severe congenital phenotype. The focus of this proposal is to use transgenic models to test the hypothesis that CUG and CCUG repeat toxicity is comparable at the cellular and organismal levels, that alterations in temporal and spatial expression of RNA expansion transcripts cause phenotypic similarities and differences in DM1 and DM2, including CNS effects, and that many of the multisystemic features of the disease are reversible.
Our specific aims are: 1) Clinical similarities and differences between DM1 and DM2 result from variations in temporal and spatial expression patterns of the CUG/CCUG expansion transcripts and are independent of both the repeat motif and flanking sequence. 2) CNS specific molecular changes found in myotonic dystrophy are caused by RNA gain of function effects and that molecular and phenotypic similarities and differences between DM1 and DM2 result from variations in temporal and spatial expression patterns of the CUG/CCUG expansions in the brain. 3) To evaluate the effects of increased Mbnll expression in skeletal muscle and the CNS by generating an inducible transgenic mouse model of Mbnll over-expression.
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