The TTN p. Tyr4418Ter mutation causes cardiomyopathy in human and mice

Objective To generate a mouse model carrying TTN tv Y4370* simulating the newly discovered human heterozygous nonsense TTN tv c.13254T>G (p.Tyr4418Ter) to supplement and improve the functional evidence of pathogenic mutation TTN tv c.13254T>G on the pathogenic type of dilated cardiomyopathy. Methods We generated 4 mice carrying TTN tv p. Y4370* through CRISPR/Cas-mediated genome engineering. Monthly serological detection, bimonthly echocardiography, and histology evaluation were carried out to observe and compare alterations of cardiac structure and function between 4 TTN +/- mice and 4 wild-type (WT) mice. Results For the two-month-old TTN +/- mice, serum glutamic-oxalacetic transaminase (AST), lactic dehydrogenase (LDH), and creatine kinase (CK) were significantly increased, the diastolic Left Ventricular Systolic Anterior Wall (LVAW), and the LV mass markedly rose, with the left ventricular volume displaying an increasing trend and Ejection Fraction (EF) and Fractional Shortening (FS) showing a decreasing trend. Besides, the histological evaluation showed that cardiac fibrosis level and positive rate of cardiac mast cell of TTN +/- mice were obviously increased compared with WT mice. Conclusions TTN tv Y4370* could lead to cardiac structure and function alterations in mice, supplementing the evidence of TTN tv c.13254T>G pathogenicity in human.