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Genes 2018, 9(2), 86; https://doi.org/10.3390/genes9020086

Characterization of TTN Novex Splicing Variants across Species and the Role of RBM20 in Novex-Specific Exon Splicing

1
College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China
2
Animal Science, University of Wyoming, Laramie, WY 82071, USA
3
Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
4
Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA
5
Department of Cell and Regenerative Biology, Department of Chemistry, Human Proteomics Program, University of Wisconsin, Madison, WI 53705, USA
*
Author to whom correspondence should be addressed.
Received: 19 December 2017 / Revised: 30 January 2018 / Accepted: 30 January 2018 / Published: 13 February 2018
(This article belongs to the Special Issue Aberrant Pre-mRNA Splicing in Disease)
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Abstract

Titin (TTN) is a major disease-causing gene in cardiac muscle. Titin (TTN) contains 363 exons in human encoding various sizes of TTN protein due to alternative splicing regulated mainly by RNA binding motif 20 (RBM20). Three isoforms of TTN protein are produced by mutually exclusive exons 45 (Novex 1), 46 (Novex 2), and 48 (Novex 3). Alternatively splicing in Novex isoforms across species and whether Novex isoforms are associated with heart disease remains completely unknown. Cross-species exon comparison with the mVISTA online tool revealed that exon 45 is more highly conserved across all species than exons 46 and 48. Importantly, a conserved region between exons 47 and 48 across species was revealed for the first time. Reverse transcript polymerase chain reaction (RT-PCR) and DNA sequencing confirmed a new exon named as 48′ in Novex 3. In addition, with primer pairs for Novex 1, a new truncated form preserving introns 44 and 45 was discovered. We discovered that Novex 2 is not expressed in the pig, mouse, and rat with Novex 2 primer pairs. Unexpectedly, three truncated forms were identified. One TTN variant with intron 46 retention is mainly expressed in the human and frog heart, another variant with co-expression of exons 45 and 46 exists predominantly in chicken and frog heart, and a third with retention of introns 45 and 46 is mainly expressed in pig, mouse, rat, and chicken. Using Rbm20 knockout rat heart, we revealed that RBM20 is not a splicing regulator of Novex variants. Furthermore, the expression levels of Novex variants in human hearts with cardiomyopathies suggested that Novexes 2 and 3 could be associated with dilated cardiomyopathy (DCM) and/or arrhythmogenic right ventricular cardiomyopathy (ARVC). Taken together, our study reveals that splicing diversity of Novex exons across species and Novex variants might play a role in cardiomyopathy. View Full-Text
Keywords: TTN; RBM20; Novex isoforms; cardiomyopathy; alternative splicing TTN; RBM20; Novex isoforms; cardiomyopathy; alternative splicing
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Chen, Z.; Song, J.; Chen, L.; Zhu, C.; Cai, H.; Sun, M.; Stern, A.; Mozdziak, P.; Ge, Y.; Means, W.J.; Guo, W. Characterization of TTN Novex Splicing Variants across Species and the Role of RBM20 in Novex-Specific Exon Splicing. Genes 2018, 9, 86.

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