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Integrated multi-omics approach revealed TTNtv c.13254T>G causing dilated cardiomyopathy in mice
Titin-truncating variant (TTNtv) is the most common genetic cause of dilated cardiomyopathy (DCM). In the previous study, we found a novel heterozygous TTNtv c.13254T>G (p.Tyr4418Ter) associated with DCM, but lacking functional evidence. The purpose of this study is to demonstrate the pathogenici...
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Published in: | PloS one 2024-10, Vol.19 (10), p.e0311670 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites |
Online Access: | Get full text |
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Summary: | Titin-truncating variant (TTNtv) is the most common genetic cause of dilated cardiomyopathy (DCM). In the previous study, we found a novel heterozygous TTNtv c.13254T>G (p.Tyr4418Ter) associated with DCM, but lacking functional evidence. The purpose of this study is to demonstrate the pathogenicity of TTNtv c.13254T>G. We constructed a mouse model with TTNtv Y4370* on exon 45 by CRISPR/Cas9-mediated genome engineering to imitate the TTNtv. c.13254T>G. Transmission electron microscope (TEM), immunohistochemistry, western blot (WB), Transcriptome sequencing (RNA-seq), and tandem Mass Tag (TMT) proteome analysis were performed on the mutant (KO) and WT mice cardiac tissue. Multi-omics association analysis was performed to observe the damages of cardiac tissue, and changes of inflammatory factors and Titin protein. TEM results showed that TTNtv Y4370* may lead to broken myofibrils, sparse myofilament structure, and broken Z-line and H-zone in many places of cardiac tissue of KO mice. Immunohistochemistry showed a significant increase in cTnT and TNF-α expression level in KO mice cardiac tissue. RNA-seq and TMT proteome enrichment analysis further strengthened that TTNtv Y4370* led to cardiac injury and inflammatory response in KO mice. In summary, TTNtv c.13254T>G contributed to the cardiac injury, inflammatory response and construct alterations in mice, that is TTNtv c.13254T>G may cause DCM in mice. These functional evidence of TTNtv c.13254T>G have important significance for follow-up genetic research of DCM in human. |
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ISSN: | 1932-6203 1932-6203 |
DOI: | 10.1371/journal.pone.0311670 |