Abstract
Our recent study indicated that RNA binding motif 20 (Rbm20) alters splicing of titin and other genes. The current goals were to understand how the Rbm20-/- rat is related to physiological, structural, and molecular changes leading to heart failure. We quantitatively and qualitatively compared the expression of titin isoforms between Rbm20-/- and wild type rats by real time RT-PCR and SDS agarose electrophoresis. Isoform changes were linked to alterations in transcription as opposed to translation of titin messages. Reduced time to exhaustion with running in knockout rats also suggested a lower maximal cardiac output or decreased skeletal muscle performance. Electron microscopic observations of the left ventricle from knockout animals showed abnormal myofibril arrangement, Z line streaming, and lipofuscin deposits. Mutant skeletal muscle ultrastructure appeared normal. The results suggest that splicing alterations in Rbm20-/- rats resulted in pathogenic changes in physiology and cardiac ultrastructure. Secondary changes were observed in message levels for many genes whose splicing was not directly affected. Gene and protein expression data indicated the activation of pathophysiological and muscle stress-activated pathways. These data provide new insights on Rbm20 function and how its malfunction leads to cardiomyopathy.
Highlights
Our group cloned a novel splicing factor, RNA binding motif 20 (Rbm20), using a natural mutant rat and found that Rbm20 regulates titin isoform transition and the splicing of 30 other genes [1,2,3]
Titin has been implicated as being responsible for passive tension, and other work has shown that the proportions of different sized titins affect passive tension [12,31,32]
These phenotypes have been observed with echocardiography in one and a half year old Rbm20-/- animals [3]
Summary
Our group cloned a novel splicing factor, RNA binding motif 20 (Rbm20), using a natural mutant rat and found that Rbm regulates titin isoform transition and the splicing of 30 other genes [1,2,3]. Rbm is one of a series of 48 putative RNA binding proteins that have been identified genomically by the presence of an RNA binding motif. Many of these proteins have been shown to be involved in RNA alternative splicing. The relationship of RBM20 mutations to human dilated cardiomyopathy was first reported by Brauch and coworkers [4]. They found five different mutations in eight families with cardiac enlargement (determined by echocardiography) and reduced ejection fraction. RBM20 mutations may account for as many as 3% of dilated cardiomyopathy patients [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
