Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients With Dilated Cardiomyopathy

Author:

Hershberger Ray E.1,Pinto Jose Renato1,Parks Sharie B.1,Kushner Jessica D.1,Li Duanxiang1,Ludwigsen Susan1,Cowan Jason1,Morales Ana1,Parvatiyar Michelle S.1,Potter James D.1

Affiliation:

1. From the Division of Cardiovascular Medicine, Department of Medicine (R.E.H., D.L., J.C., A.M.) and the Department of Molecular and Cellular Pharmacology (J.R.P., M.S.P., J.D.P.), University of Miami Miller School of Medicine, Miami, Fla; and the Division of Cardiovascular Medicine (S.B.P., J.D.K., S.L.), Oregon Health & Science University, Portland, Ore.

Abstract

Background— A key issue for cardiovascular genetic medicine is ascertaining if a putative mutation indeed causes dilated cardiomyopathy (DCM). This is critically important as genetic DCM, usually presenting with advanced, life-threatening disease, may be preventable with early intervention in relatives known to carry the mutation. Methods and Results— We recently undertook bidirectional resequencing of TNNT2 , the cardiac troponin T gene, in 313 probands with DCM. We identified 6 TNNT2 protein-altering variants in 9 probands, all who had early onset, aggressive disease. Additional family members of mutation carriers were then studied when available. Four of the 9 probands had DCM without a family history, and 5 probands had familial DCM. Only 1 mutation (Lys210del) could be attributed as definitively causative from previous reports. Four of the 5 missense mutations were novel (Arg134Gly, Arg151Cys, Arg159Gln, and Arg205Trp), and one was previously reported with hypertrophic cardiomyopathy (Glu244Asp). Based on the clinical, pedigree, and molecular genetic data, these 5 mutations were considered possibly or likely disease causing. To further clarify their potential pathophysiologic impact, we undertook functional studies of these mutations in cardiac myocytes reconstituted with mutant troponin T proteins. We observed decreased Ca 2+ sensitivity of force development, a hallmark of DCM, in support of the conclusion that these mutations are disease causing. Conclusions— We conclude that the combination of clinical, pedigree, molecular genetic, and functional data strengthen the interpretation of TNNT2 mutations in DCM.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Genetics(clinical),Cardiology and Cardiovascular Medicine,Genetics

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