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Mani
S.
Mahadevan,
M.D. [more information]
Professor of Pathology Research Interests:Molecular Mechanisms of Myotonic Muscular Dystrophy |
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Trinucleotide repeats and genetic instability |
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The Mahadevan lab is focused on studying the molecular pathogenesis of myotonic dystrophy, the most common inherited muscular dystrophy in adults. They study, myotonic dystrophy type 1(DM1). DM1 is caused by an expansion in a CTG triplet repeat in the 3' untranslated region of a gene called DM protein kinase (DMPK), and represents one of the first examples of diseases caused by trinucleotide repeat instability. Of all the triplet repeat mutations (now over 15 disorders), DM represents the most dramatic example of genomic instability, with both mitotic and meiotic instability. In normal individuals, the copy number of repeats ranges from 5 to about 30, however, in DM1 patients, the repeats range from 50 to several thousand repeats. The mechanism by which triplet repeat instability comes about is of significant interest to researchers trying to understand the mechanisms of genomic instability and several mechanisms have been proposed including DNA slippage, mismatch repair and double strand break repair. Several groups have generated mice with expanded repeat tracts and have bred them with mice with defects in these various pathways, and have found varying and somewhat surprising results, such as absence of certain mismatch repair proteins actually stabilized the repeat tract. A recent concept that has been mooted pertains to the hypothesis that the instability of the repeat tracts may be related to the transcriptional status of the locus containing the repeat tracts. That is, microsatelliltes that are part of transcriptional units may be more unstable, perhaps due to repeated unraveling of the DNA during transcription and subsequent annealing of the DNA. With regard to this, it is of note that individuals with DM1 show heterogeneity in repeat number from tissue to tissue with skeletal muscle often having the greatest degree of expansion. Skeletal and cardiac muscle are both post-mitotic tissues but have the highest degree of expression of the DMPK gene.
In their lab, they have generated inducible transgenic mice with normal [(CTG)5} and mutant [(CTG>200)] DMPK 3'UTR sequences to study the molecular pathogenesis of DM. However, these mice would also be a good model in which to address the "transcriptional state hypothesis". For example, repeat tract instability can be compared between mice that have silent transcriptional units and genetically identical mice in which the gene has been induced. Time course studies can be done to look at the kinetics of repeat instability over the lifespan of the animal. Various tissues, such as heart and skeletal muscle can be compared to each other and to tissues in which the transgene is present but not expressed due to the tissue specific nature of the promoter driving the transgene. By studying these mice they hope to provide some insight into the role of transcription in genomic instability. Dr. Mahadevan just recently joined the U.Va. faculty, but has had preliminary discussions with Dr. Dutta about future collaborations. They have used the DNA sequencing facility, the cell culture facility.
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