Mahadevan, Mani S.
- BS, Biochemistry, University of Ottawa
- MD, Medicine, University of Ottawa
- Intern, Medicine, University of Western Ontario
- Residency, Medicine, University of Ottawa
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.