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Updated: Jul 2, 2025
Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
The TTN p. Tyr4418Ter mutation causes cardiomyopathy in human and mice
Wenqiang Sun1, Xiaohui Liu2, Laichun Song1
1Division of Cardiac Surgery & Wuhan Clinical Research Center for Cardiomyopathy, Wuhan Asia Heart Hospital Affiliated with Wuhan University of Science and Technology, Wuhan, Hubei, P.R. China.
Objective:
To generate a mouse model carrying TTNtv Y4370* simulating the newly discovered human heterozygous nonsense TTNtv c.13254T>G (p.Tyr4418Ter) to supplement and improve the functional evidence of pathogenic mutation TTNtv c.13254T>G on the pathogenic type of dilated cardiomyopathy.
Methods:
We generated 4 mice carrying TTNtv 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:
TTNtv Y4370* could lead to cardiac structure and function alterations in mice, supplementing the evidence of TTNtv c.13254T>G pathogenicity in human.
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