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

Title: Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients with Dilated Cardiomyopathy.
Name(s): Hershberger, Ray, author
Pinto, Jose, author
Parks, Sharie, author
Kushner, Jessica, author
Li, Duanxiang, author
Ludwigsen, Susan, author
Cowan, Jason, author
Morales, Ana, author
Parvatiyar, Michelle, author
Potter, James, author
Type of Resource: text
Genre: Text
Issuance: serial
Date Issued: 2009
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: 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.
Identifier: FSU_migr_biomed_faculty_publications-0059 (IID), 10.1161/CIRCGENETICS.108.846733 (DOI)
Keywords: amino acid substitution, calcium, cardiomyopathy, dilated, cardiomyopathy, hypertrophic, genetic predisposition to disease, mutation, missense, pedigree, Troponin T
Uncontrolled subjects: Adolescent, Adult, Aged, Amino Acid Substitution, Calcium, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Child, Child, Preschool, Genetic Predisposition to Disease, Humans, Infant, Middle Aged, Mutation, Missense, Pedigree, Troponin T
Note: Originally published in Circulation:'>">Circulation: Cardiovascular Genetics.
Citation: Hershberger RE1, Pinto JR, Parks SB, Kushner JD, Li D, Ludwigsen S, Cowan J, Morales A, Parvatiyar MS, & Potter JD. (2009). Clinical and functional characterization of TNNT2 mutations identified in patients with dilated cardiomyopathy. Circ Cardiovasc Genet, 2(4):306-13. doi: 10.1161/CIRCGENETICS.108.846733.
Subject(s): Amino acids
Cardiovascular system -- Diseases
Inorganic compounds
Medical sciences
Persistent Link to This Record:
Owner Institution: FSU
Is Part of Series: Department of Biomedical Sciences Faculty Publications.
Is Part Of: Circulation: Cardiovascular Genetics.
Issue: 4, 2

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Hershberger, R., Pinto, J., Parks, S., Kushner, J., Li, D., Ludwigsen, S., … Potter, J. (2009). Clinical and Functional Characterization of TNNT2 Mutations Identified in Patients with Dilated Cardiomyopathy. Circulation. Retrieved from