Role of Neuron-Specific Giant Ankyrins Isoform in Developing Cardiac Arrhythmia for Myotonic Dystrophy Type 1 Patient
Abstract
Myotonic dystrophy type 1 (DM1) is a dominantly inherited disease and the second most common form of adult onset muscular dystrophy. Although skeletal muscle wasting is the major symptom, cardiac dysfunctions are the second leading cause of death in DM1, which often include conduction defects and arrhythmias. However, the precise molecular mechanisms by which trinucleotide repeat expansion causes electrophysiological and contractility abnormalities in DM1 cardiomyocytes are still not clearly understood. Ankyrins are membrane adaptor proteins that are involved in targeting and stabilization of ion channels and transporters in subcellular domains within myocytes. Human loss-of-variants and animal model studies have highlighted the in vivo roles for Ankyrins in fatal cardiac arrhythmias, which share similar pathological features with DM1. A mis-splicing mechanism in this membrane scaffolding protein Ankyrin in myotonic dystrophy patient heart leads to expression of a previously uncharacterized isoform in heart known as giant Ankyrin. These aberrantly spliced isoforms inserted a large peptide in Ankyrin regulatory C-terminal domain (CTD). The CTD has been shown to regulate the localization of its binding partners. It is in this region most pathogenic variants associated with cardiac arrhythmias were identified. In this proposal, I will investigate the underlying mechanisms of mis-splicing for large Ankyrin exons and their pathological roles in triggering cardiac arrhythmias in DM1 patients. To identify their pathological function in DM1 heart at first inducing the splice switch, I will analyze their role in cardiac arrhythmias. I will analyze their localization in cardiomyocyte membrane, targeting ion channels and their biophysical functions. Finally, to understand the splicing regulation, I will first identify the critical cis-element necessary for Ankyrin large exon splicing and then will identify the interaction with splicing factors. Therefore, finding a precise molecular mechanism underlying giant Ankyrin-mediated cardiac pathogenesis will contribute to a better understanding of the disease mechanism.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010015
Entities
People
- Chaitali Misra
Organizations
- United States Army
- University of Illinois Urbana–Champaign