Knock-In Mouse Model of Dilated Cardiomyopathy Caused by Troponin Mutation

  title={Knock-In Mouse Model of Dilated Cardiomyopathy Caused by Troponin Mutation},
  author={Cheng-Kun Du and Sachio Morimoto and Kiyomasa Nishii and Reiko Minakami and Mika Ohta and Naoto Tadano and Qun-Wei Lu and Yuan-yuan Wang and Dong-Yun Zhan and M Mochizuki and Satomi Kita and Yoshikazu Miwa and Fumi Takahashi‐Yanaga and Takahiro Iwamoto and Iwao Ohtsuki and Toshiyuki Sasaguri},
  journal={Circulation Research},
We created knock-in mice in which a deletion of 3 base pairs coding for K210 in cardiac troponin (cTn)T found in familial dilated cardiomyopathy patients was introduced into endogenous genes. Membrane-permeabilized cardiac muscle fibers from mutant mice showed significantly lower Ca2+ sensitivity in force generation than those from wild-type mice. Peak amplitude of Ca2+ transient in cardiomyocytes was increased in mutant mice, and maximum isometric force produced by intact cardiac muscle fibers… 

Figures and Tables from this paper

Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization
A gene-targeted knock-in murine model of the autosomal dominant Arg141Trp (R141W) mutation in Tnnt2 causes a Ca2+ desensitization and mice adapt by increasing Ca2-transient amplitudes, which impairs Ca2+.
Functional Analysis of a Unique Troponin C Mutation, GLY159ASP, that Causes Familial Dilated Cardiomyopathy, Studied in Explanted Heart Muscle
The differences between these data and previous in vitro results show that native phosphorylation of troponin I and Troponin T and other posttranslational modifications of sarcomeric proteins strongly influence the functional effects of a mutation.
Investigation of a transgenic mouse model of familial dilated cardiomyopathy.
Generation and Functional Characterization of Knock-in Mice Harboring the Cardiac Troponin I-R21C Mutation Associated with Hypertrophic Cardiomyopathy*
The combined effects of the R21C mutation appear to contribute toward the development of HCM and suggest that another physiological role for the phosphorylation of Ser23/Ser24 in cTnI is to prevent cardiac hypertrophy.
Inherited cardiomyopathies caused by troponin mutations
This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.
Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca²⁺ sensitivity.
It is proposed that DCM-causing mutations in thin filament proteins abolish the relationship between myofilament Ca(2+) sensitivity and troponin I phosphorylation by PKA and could be the cause of DCM in the long term.
Ca2+/Calmodulin-Dependent Kinase II&dgr; Causes Heart Failure by Accumulation of p53 in Dilated Cardiomyopathy
CaMKII&dgr; plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model.
Troponin T amino acid mutation (ΔK210) knock-in mice as a neonatal dilated cardiomyopathy model
TNNT2 ΔK210/ΔK210 mice have already developed DCM at birth, indicating that they should be an excellent animal model to identify early progression factors of DCM, and several important pathways such as cancer and focal adhesion might be associated with the pathogenesis and development of neonatal DCM.
The Role of Cardiac Troponin T Quantity and Function in Cardiac Development and Dilated Cardiomyopathy
Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype, which is related to the ratio of mutant to wildtype cTnT.


Dilated Cardiomyopathy Mutations in Three Thin Filament Regulatory Proteins Result in a Common Functional Phenotype*
The DCM mutations depress myofibrillar function, an effect fundamentally opposite to that of hypertrophic cardiomyopathy-causing thin filament mutations, suggesting that decreased contractility may trigger pathways that ultimately lead to the clinical phenotype.
Ca2+-desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy
  • S. Morimoto, Q. Lu, I. Ohtsuki
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
The present study strongly suggests that Ca2+ desensitization of force generation in sarcomere is a primary mechanism for the pathogenesis of DCM associated with the deletion mutation ΔK210 in cTnT.
Different Functional Properties of Troponin T Mutants That Cause Dilated Cardiomyopathy*
Results suggest that a rightward shift in Ca2+ sensitivity is not the only determinant for the phenotype of DCM, and circular dichroism studies suggest that the secondary structure of all three TnT mutants was similar to that of the HCWTnT.
Alterations in Thin Filament Regulation Induced by a Human Cardiac Troponin T Mutant That Causes Dilated Cardiomyopathy Are Distinct from Those Induced by Troponin T Mutants That Cause Hypertrophic Cardiomyopathy*
The functional consequences of this DCM mutation are qualitatively different from the R92Q or any other studied HCM troponin T mutation, suggesting that DCM and HCM may be triggered by distinct primary stimuli.
Ca2+-sensitizing effects of the mutations at Ile-79 and Arg-92 of troponin T in hypertrophic cardiomyopathy.
Results suggest that a heightened Ca2+ sensitivity of cardiac muscle contraction is one of the factors to cause HCM associated with these TnT mutations.
Molecular mechanisms of inherited cardiomyopathies.
Defining the role of genes in cardiac function and the mechanisms by which mutations in these genes lead to hypertrophy, dilation, and contractile failure are major goals of ongoing research.
Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy.
Conduction abnormality in gap junction protein connexin45-deficient embryonic stem cell-derived cardiac myocytes.
The results indicate that Cx45 is an essential connexin for coordinated conduction through early cardiac myocytes, and the in vitro system minimizes an influence of hemodynamic factors that complicate the phenotypes of C x45(-/-) mice.
Cardiac troponin T lysine 210 deletion in a family with dilated cardiomyopathy.
Cardiac troponin T exon 13 lysine deletions can cause FDC of varying severity and are an important but uncommon cause of FDC.