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Title:Investigation of Splicing Misregulation by Rbfox2 in Myotonic Dystrophy Type 1
Author(s):Lin, Feikai
Contributor(s):Kalsotra, Auinash
Subject(s):Molecular and Cellular Biology
RNA toxicity
Alternative Splicing
Myotonic Dystrophy
CRISPR
Abstract:Myotonic dystrophy type 1 (DM1), the most common cause of adult onset muscular dystrophy, is characterized by muscle hyperexcitability (myotonia), muscle wasting and cardiac arrhythmias. While the pathological mechanisms of myotonia and muscle wasting in DM1 have been well studied, little is known about why DM1 patients experience sudden cardiac arrhythmias. DM1 is caused by the aberrant CTG repeat expansion in the 3’UTR region of DM protein kinase (DMPK) gene. The expanded trinucleotide repeats lead to the dysfunction of many RNA binding proteins, including MBNL and CELF family of splicing factors. We have discovered that a non-muscle isoform of Rbfox2 protein, the master alternative-splicing factor for muscle tissue, is drastically upregulated in DM1 patient hearts. We hypothesized that isoform-specific Rbfox2 upregulation causes missplicing of messenger RNAs, resulting in DM1-related cardiac arrhythmias. We performed RNA-sequencing and compared the cardiac transcriptomes of Rbfox2 transgenics and DM1 mouse models. We found a large number of genes related to excitation-contraction pathway that are commonly misspliced in the hearts of Rbfox2 transgenics and DM1 mice. Using a high-resolution RT-PCR assay, I further interrogated the alternative splicing patterns of these excitation-contraction genes. We have confirmed 11 commonly impacted genes—Camk2d, Kcnd3, Tnnt2, Slc9a8, Ank2, Cttn, Scn5a, Atp2b1, Cacna2d1, Titin, and Capzb—that are misspliced in Rbfox2 overexpressing mice. We are currently characterizing the functional impact of such missplicing on the encoded proteins and testing their pathogenic roles in DM1 cardiac arrhythmias and dysfunctions.
Issue Date:2018-04
Genre:Conference Poster
Type:Image
URI:http://hdl.handle.net/2142/100018
Rights Information:Copyright 2018 Feikai Lin
Date Available in IDEALS:2018-05-23


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