Mani S. Mahadevan
- BS, University of Ottawa
- MD, University of Ottawa
- Intern, University of Western Ontario
- Residency, University of Ottawa
- Professor, Pathology
- Phone: 243-4816
- Email: email@example.com
Molecular Mechanisms of Myotonic Muscular Dystrophy
Our research is in the field of human genetics. Specifically, we are studying the molecular genetics and biology of myotonic dystrophy (DM), the most common inherited neuromuscular disorder in adults. We have previously cloned the gene for DM and identified the DM mutation as a CTG trinucleotide repeat expansion in the 3’ untranslated region of a gene encoding a serine-threonine protein kinase (DMPK). The DM mutation was one of the first members of growing family of triplet repeat mutations causing human disease. However, the mechanism by which it causes disease is unknown. We are studying the effects of the DM mutation on gene expression and RNA metabolism. These studies involve the establishment of cell culture and transgenic mouse models of disease pathogenesis, the identification and characterization of RNA-binding proteins interacting with the DMPK transcript, and studying the role of the mutant DMPK 3’UTR mRNA in inhibiting normal muscle development. Our data shows that the mutant DMPK 3’UTR mRNA is trapped as distinct foci in the nucleus, and that its expression is sufficient to inhibit normal muscle differentiation. Our long-term goals are to understand the molecular mechanisms underlying DM and the establishment of model systems with which new approaches to therapeutic intervention could be developed and studied. Furthermore, the study of the DM mutation has led to an active research program in RNA processing, RNA transport and muscle development.
- Foff E, Mahadevan M. Therapeutics development in myotonic dystrophy type 1. Muscle Nerve. 44(2): 160-9. PMCID: PMC3136655
- Sabouri L, Mahadevan M, Narang M, Lee D, Surh L, Korneluk R. Effect of the myotonic dystrophy (DM) mutation on mRNA levels of the DM gene. Nature genetics. 1993;4(3): 233-8. PMID: 8358430
- Mahadevan M, Amemiya C, Jansen G, Sabourin L, Baird S, Neville C, Wormskamp N, Segers B, Batzer M, Lamerdin J. Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene. Human molecular genetics. 1993;2(3): 299-304. PMID: 8499920
- Amack J, Paguio A, Mahadevan M. Cis and trans effects of the myotonic dystrophy (DM) mutation in a cell culture model. Human molecular genetics. 1999;8(11): 1975-84. PMID: 10484765
- Tiscornia G, Mahadevan M. Myotonic dystrophy: the role of the CUG triplet repeats in splicing of a novel DMPK exon and altered cytoplasmic DMPK mRNA isoform ratios. Molecular cell. 2000;5(6): 959-67. PMID: 10911990
- Amack J, Mahadevan M. The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation. Human molecular genetics. 2001;10(18): 1879-87. PMID: 11555624
- Amack J, Reagan S, Mahadevan M. Mutant DMPK 3'-UTR transcripts disrupt C2C12 myogenic differentiation by compromising MyoD. The Journal of cell biology. 2002;159(3): 419-29. PMID: 12427866 | PMCID: PMC2173077
- Mastroyiannopoulos N, Feldman M, Uney J, Mahadevan M, Phylactou L. Woodchuck post-transcriptional element induces nuclear export of myotonic dystrophy 3' untranslated region transcripts. EMBO reports. 2005;6(5): 458-63. PMID: 15832171 | PMCID: PMC1299300
- Mahadevan M, Yadava R, Yu Q, Balijepalli S, Frenzel-McCardell C, Bourne T, Phillips L. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nature genetics. 2006;38(9): 1066-70. PMID: 16878132 | PMCID: PMC2909745
- Mahadevan M, Yadava R, Yu Q, Balijepalli S, Frenzel-McCardell C, Bourne T, Phillips L. Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy. Nat Genet. 38(9): 1066-70. PMCID: PMC2909745
- Yadava R, Frenzel-McCardell C, Yu Q, Srinivasan V, Tucker A, Puymirat J, Thornton C, Prall O, Harvey R, Mahadevan M. RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression. Nature genetics. 2007;40(1): 61-8. PMID: 18084293 | PMCID: PMC2909759
- Mastroyiannopoulos N, Chrysanthou E, Kyriakides T, Uney J, Mahadevan M, Phylactou L. The effect of myotonic dystrophy transcript levels and location on muscle differentiation. Biochemical and biophysical research communications. 2008;377(2): 526-31. PMID: 18930030
- Yadava R, Frenzel-McCardell C, Yu Q, Srinivasan V, Tucker A, Puymirat J, Thornton C, Prall O, Harvey R, Mahadevan M. RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression. Nat Genet. 2008;40(1): 61-8. PMCID: PMC2909759
- Chute D, Cousar J, Mahadevan M, Siegrist K, Silverman L, Stoler M. Detection of immunoglobulin heavy chain gene rearrangements in classic hodgkin lymphoma using commercially available BIOMED-2 primers. Diagn Mol Pathol. 2008;17(2): 65-72.
- Genetics. Exposing a DUX tale. Science (New York, N.Y.). 2010;329(5999): 1607-8. PMID: 20929834
- Genetics. Exposing a DUX tale. Science. 329(5999): 1607-8.
- Myotonic muscular dystrophy, RNA toxicity, and the brain: trouble making the connection? Cell Stem Cell. 8(4): 349-50.