MOLECULAR PATHOGENESIS OF MYOTONIC DYSTROPHY

Summary

Principal Investigator: THOMAS ALEXANDER COOPER
Abstract: ABSTRACT Myotonic dystrophy (DM) is the second most common cause of muscular dystrophy and the most common cause of adult onset muscular dystrophy. The disease is dominantly inherited, multisystemic, and phenotypically variable. The mutations that cause DM are expanded tri- (CTG) and tetra- (CCTG) nucleotide repeats located within untranslated regions of transcribed genes. Pathogenesis involves a novel mechanism in which RNA transcribed from the expanded allele exerts a toxic gain-of-function. Recent evidence indicates that an RNA gain-of-function is an important component of other microsatellite expansion disorders such as Spinocerebellar Ataxia 8 (SCA8), Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), and Huntington Disease-Like 2 (HDL2). One mechanism by which the expanded repeat RNA exerts a gain-of-function in DM is by sequestration of RNA binding proteins such as the muscleblind-like (MBNL) family, resulting in a loss-of-function. We have identified a second mechanism in which expanded repeat RNA activates protein kinase C (PKC) and induces PKC-dependent phosphorylation of a second RNA binding protein, CUG-binding protein 1 (CUGBP1), resulting in its stabilization and up-regulation. MBNL and CUGBP1 normally regulate pre-mRNA alternative splicing during development and the disruption of their functions in DM results in the splicing defects that have previously been linked with causation of disease symptoms. The finding that RNA from a microsatellite expansion induces a signaling event has broad implications to the mechanism of pathogenesis. The goals of this proposal are to determine the mechanism by which expanded repeat RNA activates a signaling event, investigate the immediate effects on CUGBP1 function, determine the broader consequences, and relate these effects of the expanded repeats to mechanisms of inhibited skeletal muscle differentiation in cell culture and wasting of skeletal muscle tissue. The latter aspect of the investigation will be performed using a newly developed DM1 mouse model that reproduces features of the disease including severe skeletal muscle wasting. At the completion of these studies, we will have established the contributions to disease pathogenesis of a newly discovered signaling event stimulated by microsatellite-derived RNA. These results will provide new therapeutic targets to prevent or circumvent the molecular events leading to muscle wasting.
Funding Period: 1999-02-08 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. ncbi Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1
    Olivier Leroy
    INSERM U422, Pl de Verdun 59045 Lille Cedex France
    Biochim Biophys Acta 1762:460-7. 2006
  2. pmc CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1
    Amanda J Ward
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Hum Mol Genet 19:3614-22. 2010
  3. pmc Identification of MBNL1 and MBNL3 domains required for splicing activation and repression
    Ioannis Grammatikakis
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Nucleic Acids Res 39:2769-80. 2011
  4. pmc Alternative splicing dysregulation secondary to skeletal muscle regeneration
    James P Orengo
    Department of Pathology and Immunology and, Baylor College of Medicine Houston, TX 77030, USA
    Ann Neurol 69:681-90. 2011
  5. pmc Myotonic dystrophy mouse models: towards rational therapy development
    Mário Gomes-Pereira
    INSERM U781, Universite Paris Descartes, Faculte de Medicine Necker Enfants Malades, Paris, France
    Trends Mol Med 17:506-17. 2011
  6. pmc Functional consequences of developmentally regulated alternative splicing
    Auinash Kalsotra
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
    Nat Rev Genet 12:715-29. 2011
  7. pmc RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1
    Johanna E Lee
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 109:4221-6. 2012
  8. pmc RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity
    Gloria V Echeverria
    Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Brain Res 1462:100-11. 2012
  9. pmc Pre-mRNA splicing in disease and therapeutics
    Ravi K Singh
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Trends Mol Med 18:472-82. 2012
  10. pmc Antisense oligonucleotides: rising stars in eliminating RNA toxicity in myotonic dystrophy
    Zhihua Gao
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Hum Gene Ther 24:499-507. 2013

Detail Information

Publications30

  1. ncbi Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1
    Olivier Leroy
    INSERM U422, Pl de Verdun 59045 Lille Cedex France
    Biochim Biophys Acta 1762:460-7. 2006
    ..Altogether, these results show the importance of determining all the exons and organs targeted by mis-splicing to determine the dysregulation mechanisms of mis-splicing in DM1...
  2. pmc CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1
    Amanda J Ward
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Hum Mol Genet 19:3614-22. 2010
    ..Adult mouse skeletal muscle overexpressing CUGBP1 reproduces molecular and physiological defects of DM1 tissue. The results from this study strongly suggest that CUGBP1 has a major role in DM1 skeletal muscle pathogenesis...
  3. pmc Identification of MBNL1 and MBNL3 domains required for splicing activation and repression
    Ioannis Grammatikakis
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Nucleic Acids Res 39:2769-80. 2011
    ..These results have identified protein domains required for splicing repression and activation and provide insight into the mechanism of splicing regulation by MBNL proteins...
  4. pmc Alternative splicing dysregulation secondary to skeletal muscle regeneration
    James P Orengo
    Department of Pathology and Immunology and, Baylor College of Medicine Houston, TX 77030, USA
    Ann Neurol 69:681-90. 2011
    ....
  5. pmc Myotonic dystrophy mouse models: towards rational therapy development
    Mário Gomes-Pereira
    INSERM U781, Universite Paris Descartes, Faculte de Medicine Necker Enfants Malades, Paris, France
    Trends Mol Med 17:506-17. 2011
    ..More importantly, it provides critical assessment of their suitability and limitations for preclinical testing of emerging therapeutic strategies...
  6. pmc Functional consequences of developmentally regulated alternative splicing
    Auinash Kalsotra
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
    Nat Rev Genet 12:715-29. 2011
    ..Alternative splicing can drive determinative physiological change or can have a permissive role by providing mRNA variability that is used by other regulatory mechanisms...
  7. pmc RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1
    Johanna E Lee
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 109:4221-6. 2012
    ..Additional optimization will be required for systemic delivery; however, our study provides an alternative strategy for the use of ASOs in DM1 therapy...
  8. pmc RNA-binding proteins in microsatellite expansion disorders: mediators of RNA toxicity
    Gloria V Echeverria
    Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Brain Res 1462:100-11. 2012
    ..We will discuss approaches that have characterized the toxic contributions of these various factors...
  9. pmc Pre-mRNA splicing in disease and therapeutics
    Ravi K Singh
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Trends Mol Med 18:472-82. 2012
    ..In addition to discussing the disorders caused by these mutations, this review summarizes therapeutic approaches that have emerged to correct splicing of individual genes or target the splicing machinery...
  10. pmc Antisense oligonucleotides: rising stars in eliminating RNA toxicity in myotonic dystrophy
    Zhihua Gao
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Hum Gene Ther 24:499-507. 2013
    ..ASO targeting approaches will also provide avenues for the treatment of other repeat RNA-mediated diseases...
  11. pmc Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy
    Zhihua Gao
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 110:13570-5. 2013
    ..We propose that PKM2 expression induces changes in type 1 fibers associated with muscle atrophy and muscle weakness in DM1. ..
  12. pmc Muscleblind-like 1 activates insulin receptor exon 11 inclusion by enhancing U2AF65 binding and splicing of the upstream intron
    Gloria V Echeverria
    Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, TX 77030, USA, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA and Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA
    Nucleic Acids Res 42:1893-903. 2014
    ..These results suggest that MBNL1 directly activates binding of U2AF65 to enhance upstream intron removal to ultimately activate alternative exon inclusion. ..
  13. pmc The Mef2 transcription network is disrupted in myotonic dystrophy heart tissue, dramatically altering miRNA and mRNA expression
    Auinash Kalsotra
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA
    Cell Rep 6:336-45. 2014
    ..We conclude that loss of MEF2 in DM1 heart causes pathogenic features through aberrant expression of both miRNA and mRNA targets. ..
  14. pmc Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1
    Misha Koshelev
    Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
    Hum Mol Genet 19:1066-75. 2010
    ..These results strongly support a role for CUGBP1 up-regulation in DM1 pathogenesis...
  15. pmc The pathobiology of splicing
    Amanda J Ward
    Departments of Molecular and Cellular Biology and Pathology, Baylor College of Medicine, Houston, TX 77030, USA
    J Pathol 220:152-63. 2010
    ..An understanding of the role of splicing in disease expands potential opportunities for therapeutic intervention by either directly addressing the cause or by providing novel approaches to circumvent disease processes...
  16. ncbi MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1
    Maria de Haro
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
    Hum Mol Genet 15:2138-45. 2006
    ..Perhaps more importantly, they also provide proof of the principle that CUG-induced muscle toxicity can be suppressed...
  17. ncbi RNA-mediated neuromuscular disorders
    Laura P W Ranum
    Institute of Human Genetics and Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Annu Rev Neurosci 29:259-77. 2006
    ....
  18. pmc A bichromatic fluorescent reporter for cell-based screens of alternative splicing
    James P Orengo
    Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
    Nucleic Acids Res 34:e148. 2006
    ....
  19. ncbi Expression, localization and tau exon 10 splicing activity of the brain RNA-binding protein TNRC4
    J Paul Chapple
    MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King s College London, De Crespigny Park, London SE5 8AF, UK
    Hum Mol Genet 16:2760-9. 2007
    ..This study represents the first characterization of TNRC4 and provides further insight into the mechanisms of brain-specific alternative splicing and their possible pathological implications...
  20. pmc Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy
    Guey Shin Wang
    Department of Pathology, Baylor College of Medicine, Houston, Texas, USA
    J Clin Invest 117:2802-11. 2007
    ..These results indicate that CUGBP1 upregulation is an early and primary response to expression of CUG repeat RNA...
  21. pmc Increased steady-state levels of CUGBP1 in myotonic dystrophy 1 are due to PKC-mediated hyperphosphorylation
    N Muge Kuyumcu-Martinez
    Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
    Mol Cell 28:68-78. 2007
    ..These results indicate that inappropriate activation of the PKC pathway contributes to the pathogenic effects of a noncoding RNA...
  22. ncbi Overexpression of MBNL1 fetal isoforms and modified splicing of Tau in the DM1 brain: two individual consequences of CUG trinucleotide repeats
    C M Dhaenens
    INSERM, U837, Place de Verdun, 59045 Lille, France
    Exp Neurol 210:467-78. 2008
    ..The modified splicing of Tau thus results from a possibly CUG-mediated loss of function of MBNL1, but not from changes in the MBNL1 expression pattern...
  23. pmc Expanded CTG repeats within the DMPK 3' UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy
    James P Orengo
    Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
    Proc Natl Acad Sci U S A 105:2646-51. 2008
    ..Our results indicate that increased CUGBP1 protein levels are associated with DMPK-CUG RNA expression, suggesting a role for CUGBP1-specific splicing or cytoplasmic functions in muscle wasting...
  24. pmc RNA and disease
    Thomas A Cooper
    Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
    Cell 136:777-93. 2009
    ..The discovery of disease-causing mutations in RNAs is yielding a wealth of new therapeutic targets, and the growing understanding of RNA biology and chemistry is providing new RNA-based tools for developing therapeutics...
  25. pmc PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1
    Guey Shin Wang
    Department of Pathology, Baylor College of Medicine, Houston, Texas, USA
    J Clin Invest 119:3797-806. 2009
    ..Our results suggest that pharmacological blockade of PKC activity mitigates the DM1 cardiac phenotype and provide strong evidence for a role for the PKC pathway in DM1 pathogenesis...
  26. pmc Pathogenic mechanisms of myotonic dystrophy
    Johanna E Lee
    Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
    Biochem Soc Trans 37:1281-6. 2009
    ..This review will focus on the RNA gain-of-function disease mechanism, the important roles of MBNL1 and CUGBP1 in DM1, and the relevance to other RNA dominant disorders...
  27. pmc Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development
    Jimena Giudice
    Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA
    Nat Commun 5:3603. 2014
    ..These results identify potential roles for AS in multiple aspects of postnatal heart maturation, including vesicular trafficking and intracellular membrane dynamics. ..

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. Mechanisms of Adaptation to Exercise in Health and COPD
    Peter D Wagner; Fiscal Year: 2013
    ....
  3. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  4. Role of pre-mRNA alternative splicing programs in heart and muscle development
    ANDREA NICOLE LADD; Fiscal Year: 2013
    ..Furthermore, these studies will shed light on how disruption of normal alternative splicing contributes to disease states resulting from developmental perturbation ..
  5. Deciphering the role of the RNA-binding protein, FXR1, in cardiac muscle assembly
    Carol C Gregorio; Fiscal Year: 2013
    ..Furthermore, the discovery of mRNA targets regulated by FXR1 during normal development and in diseased states may identify novel therapeutic approaches for heart disease. ..
  6. The Pathogenesis of Facioscapulohumeral Muscular Dystrophy
    Stephen J Tapscott; Fiscal Year: 2013
    ..Together, these studies combine genetic, epigenetic, transcriptional and developmental approaches to defining the molecular deficits that cause FSHD and will provide a new basis for developing therapies. ..
  7. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  8. Transcriptome processing networks in skeletal muscle: mechanisms and functions
    THOMAS ALEXANDER COOPER; Fiscal Year: 2013
    ..This information will be used to understand normal processes in skeletal muscle useful for future development of therapeutic approaches to reverse or circumvent disease. ..
  9. Arterial Dysfunction: Basic and Clinical Mechanisms
    Thomas Michel; Fiscal Year: 2013
    ..Gladyshev. P. Libby directs the Redox Biomarkers Core;metabolic characterizations of mouse models studied in this Program will take place at the Yale Mouse Metabolic Phenotyping Center, led by G. Shulman. ..