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J. Biol. Chem., Vol. 283, Issue 4, 2156-2166, January 25, 2008

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A Troponin T Mutation That Causes Infantile Restrictive Cardiomyopathy Increases Ca²⁺ Sensitivity of Force Development and Impairs the Inhibitory Properties of Troponin^*

From the Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida 33136

Restrictive cardiomyopathy (RCM) is a rare disorder characterized by impaired ventricular filling with decreased diastolic volume. We are reporting the functional effects of the first cardiac troponin T (CTnT) mutation linked to infantile RCM resulting from a de novo deletion mutation of glutamic acid 96. The mutation was introduced into adult and fetal isoforms of human cardiac TnT (HCTnT3-E96 and HCTnT1-E106, respectively) and studied with either cardiac troponin I (CTnI) or slow skeletal troponin I (SSTnI). Skinned cardiac fiber measurements showed a large leftward shift in the Ca²⁺ sensitivity of force development with no differences in the maximal force. HCTnT1-E106 showed a significant increase in the activation of actomyosin ATPase with either CTnI or SSTnI, whereas HCTnT3-E96 was only able to increase the ATPase activity with CTnI. Both mutants showed an impaired ability to inhibit the ATPase activity. The capacity of the CTnI·CTnC and SSTnI·CTnC complexes to fully relax the fibers after TnT displacement was also compromised. Experiments performed using fetal troponin isoforms showed a less severe impact compared with the adult isoforms, which is consistent with the cardioprotective role of SSTnI and the rapid onset of RCM after birth following the isoform switch. These data indicate that troponin mutations related to RCM may have specific functional phenotypes, including large leftward shifts in the Ca²⁺ sensitivity and impaired abilities to inhibit ATPase and to relax skinned fibers. All of this would account for and contribute to the severe diastolic dysfunction seen in RCM.

Received for publication, August 22, 2007 , and in revised form, November 16, 2007.

^* This work was supported by National Institutes of Health Grants HL-674154 and HL-42325. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Dept. of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, 1600 NW 10th Ave. (R-189), Miami, FL 33136. Tel.: 305-243-5874; Fax: 305-324-6024; E-mail: jdpotter{at}miami.edu.

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