{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T04:22:36Z","timestamp":1747196556401,"version":"3.40.5"},"reference-count":23,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T00:00:00Z","timestamp":1728000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Special Project of Hubei Provincial Health Commission","award":["WJ2021M033"],"award-info":[{"award-number":["WJ2021M033"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Titin-truncating variant (<jats:italic>TTNtv<\/jats:italic>) is the most common genetic cause of dilated cardiomyopathy (DCM). In the previous study, we found a novel heterozygous <jats:italic>TTN<\/jats:italic>tv c.13254T&gt;G (p.Tyr4418Ter) associated with DCM, but lacking functional evidence. The purpose of this study is to demonstrate the pathogenicity of <jats:italic>TTNtv<\/jats:italic> c.13254T&gt;G. We constructed a mouse model with <jats:italic>TTN<\/jats:italic>tv Y4370* on exon 45 by CRISPR\/Cas9-mediated genome engineering to imitate the <jats:italic>TTN<\/jats:italic>tv. c.13254T&gt;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 <jats:italic>TTNtv<\/jats:italic> 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-\u03b1 expression level in KO mice cardiac tissue. RNA-seq and TMT proteome enrichment analysis further strengthened that <jats:italic>TTNtv<\/jats:italic> Y4370* led to cardiac injury and inflammatory response in KO mice. In summary, <jats:italic>TTNtv<\/jats:italic> c.13254T&gt;G contributed to the cardiac injury, inflammatory response and construct alterations in mice, that is <jats:italic>TTNtv<\/jats:italic> c.13254T&gt;G may cause DCM in mice. These functional evidence of <jats:italic>TTNtv<\/jats:italic> c.13254T&gt;G have important significance for follow-up genetic research of DCM in human.<\/jats:p>","DOI":"10.1371\/journal.pone.0311670","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T17:22:59Z","timestamp":1728062579000},"page":"e0311670","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated multi-omics approach revealed TTNtv c.13254T&gt;G causing dilated cardiomyopathy in 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