Auinash Kalsotra, assistant professor and Beckman Fellow at the University of Illinois at Urbana-Champaign, was awarded an MDA research grant totaling $300,000 over three years to shed light on how defects develop in the heart in type 1 myotonic dystrophy (DM1).
Please describe your current research.
DM1 is caused by an unusual mutation in which a small DNA segment of the mutated gene is repeated hundreds of times. The mutated gene, when copied into RNA, becomes toxic and particularly harmful because instead of its normal exit to the cytoplasm, the RNA with repeats gets trapped within the nucleus. This alters the normal function of many genes, not just the gene with the mutation. While the mutation affects multiple tissues, cardiac defects are the second leading cause of death amongst DM1 individuals; however, the molecular mechanism(s) responsible for the cardiac pathogenesis remain poorly understood.
We have discovered that in DM1-diseased heart, the fetal non-muscle isoform of an RNA binding protein called RBFOX2 is significantly upregulated. By forcing the expression of the non-muscle isoform of RBFOX2 in wildtype adult mouse heart, we have reproduced many of the cardiac dysfunctions observed in DM1, including arrhythmias and cardiac conduction defects.
In our current work, we aim to determine how the balance between muscle and non-muscle isoforms for RBFOX2 is achieved during normal heart development. We will further investigate how this regulation is disrupted in DM1 and why the selective expression of non-muscle RBFOX2 isoform triggers a cardiac disease phenotype.
What inspired you to study myotonic dystrophy?
I got interested in studying RNA biology about 10 years ago. This was the period when it had become clear that DM1 is caused by a trinucleotide repeat expansion in the “non-coding” region of a gene. What it meant was that the mutation only affects RNA but not the protein that is encoded by the gene. This was a new way of thinking about human disease, as most other studies focused on proteins.
What is your focus within the myotonic dystrophy field, and why is it important?
The current focus of my group is to determine the underlying mechanisms that promote cardiac arrhythmias in DM1 patients.
While DM1 is a neuromuscular disease affecting many organ systems, cardiac dysfunctions including arrhythmias are the second leading cause of death amongst DM1 individuals. The molecular mechanism(s) responsible; however, remain poorly understood.
What is the expected outcome of your research?
We expect that our research will not only enhance the basic understanding of DM1 cardiac pathogenesis but also reveal the cellular functions of RBFOX2 splice variants in the heart.
How will your research lead to treatments and cures?
The findings are expected to offer insights into previously unknown mechanisms causing arrhythmias and will help us explore new approaches for treating DM1 patients.
What do you feel people impacted by myotonic dystrophy can have the most hope about with respect to research right now?
I feel that the DM field is making impressive strides in deciphering the exact pathogenic mechanisms unleashed by the trinucleotide repeat expansion. This knowledge will undoubtedly lead to the development of new treatment modalities for this debilitating disease.
To learn more about MDA research in myotonic dystrophy, visit mda.org.
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