Mani S. Mahadevan, M.D.
Medical School: University of Ottawa, Ottawa, Canada. 1986
Internship: Victoria Hospital, London, Ontario, Canada. 1986-1987
Residency: University of Ottawa, Ottawa, Canada. 1987-1991
Research Fellowship: Children’s Hospital of Eastern Ontario (CHEO), Ottawa, Canada. 1991-1995
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.
- Yadava RS, Foff EP, Yu Q, Gladman JT, Kim YK, Bhatt KS, Thornton CA, Zheng TS, Mahadevan MS: TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. Hum Mol Genet 2015, 24:2035-2048. http://www.ncbi.nlm.nih.gov/pubmed/25504044. DOI: 10.1093/hmg/ddu617.
Gladman JT, Yadava RS, Mandal M, Yu Q, Kim YK, Mahadevan MS: NKX2-5, a modifier of skeletal muscle pathology due to RNA toxicity. Hum Mol Genet 2015, 24:251-264.http://www.ncbi.nlm.nih.gov/pubmed/25168381. DOI: 10.1093/hmg/ddu443.
Kim YK, Mandal M, Yadava RS, Paillard L, Mahadevan MS: Evaluating the effects of CELF1 deficiency in a mouse model of RNA toxicity. Hum Mol Genet 2014, 23:293-302.http://www.ncbi.nlm.nih.gov/pubmed/24001600. DOI: 10.1093/hmg/ddt419.
Rehman S, Gladman JT, Periasamy A, Sun Y, Mahadevan MS: Development of an AP-FRET based analysis for characterizing RNA-protein interactions in myotonic dystrophy (DM1). PLoS One 2014, 9:e95957.http://www.ncbi.nlm.nih.gov/pubmed/24781112. DOI: 10.1371/journal.pone.0095957.
Gladman JT, Mandal M, Srinivasan V, Mahadevan MS: Age of onset of RNA toxicity influences phenotypic severity: evidence from an inducible mouse model of myotonic dystrophy (DM1). PLoS One 2013, 8:e72907.http://www.ncbi.nlm.nih.gov/pubmed/24039817. DOI: 10.1371/journal.pone.0072907.
Mahadevan MS: Myotonic dystrophy: is a narrow focus obscuring the rest of the field? Curr Opin Neurol 2012, 25:609-613. http://www.ncbi.nlm.nih.gov/pubmed/22892953. DOI: 10.1097/WCO.0b013e328357b0d9.
M Foff EP, Mahadevan MS: Therapeutics development in myotonic dystrophy type 1. Muscle Nerve 2011, 44:160-169. http://www.ncbi.nlm.nih.gov/pubmed/21607985. DOI: 10.1002/mus.22090.
Ravel-Chapuis A, BÃ©langer G, Yadava RS, Mahadevan MS, DesGroseillers L, CÃ´tÃ© J, Jasmin BJ: The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing. J Cell Biol 2012, 196:699-712. http://www.ncbi.nlm.nih.gov/pubmed/22431750. DOI: 10.1083/jcb.201108113.
Mahadevan MS: Myotonic muscular dystrophy, RNA toxicity, and the brain: trouble making the connection? Cell Stem Cell 2011, 8:349-350. http://www.ncbi.nlm.nih.gov/pubmed/21474094. DOI: 10.1016/j.stem.2011.03.007.
Mahadevan MS: Genetics. Exposing a DUX tale. Science 2010, 329:1607-1608.http://www.ncbi.nlm.nih.gov/pubmed/20929834. DOI: 10.1126/science.1195984.
Mastroyiannopoulos NP, Chrysanthou E, Kyriakides TC, Uney JB, Mahadevan MS, Phylactou LA: The effect of myotonic dystrophy transcript levels and location on muscle differentiation. Biochem Biophys Res Commun 2008, 377:526-531. http://www.ncbi.nlm.nih.gov/pubmed/18930030. DOI: 10.1016/j.bbrc.2008.10.031.
- Chute DJ, Cousar JB, Mahadevan MS, Siegrist KA, Silverman LM, Stoler MH: Detection of immunoglobulin heavy chain gene rearrangements in classic hodgkin lymphoma using commercially available BIOMED-2 primers. Diagn Mol Pathol 2008, 17:65-72. http://www.ncbi.nlm.nih.gov/pubmed/18382369. DOI: 10.1097/PDM.0b013e318150d695.
A more complete list of Dr. Mahadevan’s publications can be obtained from PubMed.