RNA binding proteins (RBPs) are highly abundant in eukaryotic cells and govern essential aspects of cellular function through interactions with their mRNA substrates and proteins. These ribonucleoprotein (RNP) complexes may further assemble into membraneless condensates, referred to as RNP granules, to regulate the localization and functions throughout RNA splicing, transcription and stability. The dysregulation of RBPs such as genetic mutations can lead to the formation of pathologic condensates. Dysregulated RNP granules have been linked to neuromuscular degenerative disease, but haven’t been linked to cardiomyopathies. RNA binding motif 20 (RBM20) is one of the RBPs that is primarily expressed in heart muscle tissue. RBM20 is a major splicing regulator of gene TTN, encoding a giant sarcomere protein titin that plays a determinant role of ventricular wall stiffness. Deficiency of RBM20 in animal models resulted in larger titin isoform expression and dilated cardiomyopathy. Recently, our lab reported that RBM20 genetic mutations in arginine/serine (RS) domain led to impaired nuclear retention and transport of RBM20 from the nucleus to the cytoplasm. Re-localization of RBM20 in the cytoplasm promoted RNP granules formation. Our mutation knock-in (KI) mouse model demonstrated severe dilated cardiomyopathy and heart failure. The mice carrying the mutation had about 50% death rate at about 8-week-old. We also observed that differentially expressed and spliced genes were associated with arrhythmia, cardiomyopathy, and sudden death. KI mice showed a reduction of diastolic stiffness and impaired contractility at both the left ventricular chamber and cardiomyocyte levels. Our results indicate that the RBM20 mutation leads to RNP granules causing severe heart failure and early death. This finding confirms the novel concept that RBM20 cardiomyopathy is a RNP granule disease.
Dr. Wei Guo received his bachelor’s degree in Biological Science in 1999 and his Ph.D. degree in Molecular and Cellular Biology in 2004 at China Agriculture University. He then moved to University of Wisconsin-Madison for his postdoctoral training from 2005 to 2010. After his postdoc training, he worked as a scientist in Medical School at University of Wisconsin-Madison from 2010 to 2013. He then became a faculty member at Department of Animal Science at University of Wyoming from 2013 to 2019. He currently is a tenure-track faculty member at Department of Animal and Dairy Sciences at University of Wisconsin-Madison. He received several scientific presentation award and Outstanding Young Investigator Award at University of Wyoming in 2018. He has published over 50 peer-reviewed articles and book-chapters. He serves as a journal reviewer for over 30 peer-reviewed journals as well as a grant reviewer in study sections for American Heart Association, NASA Human Research Program, and NIH etc. His research interests is to define the molecular and cellular mechanisms of RNA binding proteins in muscle function and disease through performing rigorous and clinically relevant research. His research is supported by the National Institutes of Health (NIH), the American Heart Association (AHA) and the United States Department of Agriculture (USDA)-NIFA Hatch grant.