Sudden death due to troponin T mutations

University of Stellenbosch, Tygerberg, Republic of South Africa.

OBJECTIVES: This study was designed to verify initial observations of the clinical and prognostic features of hypertrophic cardiomyopathy caused by cardiac tropnin T gene mutations. BACKGROUND: The most common cause of sudden cardiac death in the young is hypertrophic cardiomyopathy, which is usually familial. Mutations causing familial hypertrophic cardiomyopathy have been identified in a number of contractile protein genes, raising the possibility of genetic screening for subjects at risk. A previous report suggested that mutations in the cardiac troponin T gene were notable because they were associated with a particularly poor prognosis but only mild hypertrophy. Given the variability of some genotype:phenotype correlations, further analysis of cardiac troponin T mutations has been a priority. METHODS: Deoxyribonucleic acid from subjects with hypertrophic cardiomyopathy was screened for cardiac troponin T mutations using a ribonuclease protection assay. Polymerase chain reaction-based detection of a novel mutation was used to genotype members of two affected pedigrees. Gene carriers were examined by echocardiography and electrocardiology, and a family history was obtained. RESULTS: A novel cardiac troponin T gene mutation, arginine 92 tryptophan, was identified in 19 of 48 members of two affected pedigrees. The clinical phenotype was characterized by minimal hypertrophy (mean [+/-SD] maximal ventricular wall thickness 11.3 +/- 5.4 mm) and low disease penetrance by clinical criteria (40% by echocardiography) but a high incidence of sudden cardiac death (mean age 17 +/- 9 years). CONCLUSIONS: These data support the observation that apparently diverse cardiac troponin T gene mutations produce a consistent disease phenotype. Because this is one of poor prognosis, despite deceptively mild or undetectable hypertrophy, genotyping at this locus may be particularly informative in patient management and counselling.

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				B. J. Maron, H. Niimura, S. A. Casey, M. K. Soper, G. B. Wright, J. G. Seidman, and C. E. Seidman Development of left ventricular hypertrophy in adults with hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations J. Am. Coll. Cardiol., August 1, 2001; 38(2): 315 - 321. [Abstract] [Full Text] [PDF]

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				D. Fatkin, R. M. Graham, P. Spirito, and B. J. Maron Prognostic Value of Left Ventricular Hypertrophy in Hypertrophic Cardiomyopathy N. Engl. J. Med., January 4, 2001; 344(1): 63 - 65. [Full Text] [PDF]

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				C. Y. Ho, H. M. Lever, R. DeSanctis, C. F. Farver, J. G. Seidman, and C. E. Seidman Homozygous Mutation in Cardiac Troponin T : Implications for Hypertrophic Cardiomyopathy Circulation, October 17, 2000; 102(16): 1950 - 1955. [Abstract] [Full Text] [PDF]

				L. G D'CRUZ, C. BABOONIAN, H. E PHILLIMORE, R. TAYLOR, P. M ELLIOTT, A. VARNAVA, F. DAVISON, W. J MCKENNA, and N. D CARTER Cytosine methylation confers instability on the cardiac troponin T gene in hypertrophic cardiomyopathy J. Med. Genet., September 1, 2000; 37(9): 18e - 18. [Full Text]

				H. Kokado, M. Shimizu, H. Yoshio, H. Ino, K. Okeie, Y. Emoto, T. Matsuyama, M. Yamaguchi, T. Yasuda, N. Fujino, et al. Clinical Features of Hypertrophic Cardiomyopathy Caused by a Lys183 Deletion Mutation in the Cardiac Troponin I Gene Circulation, August 8, 2000; 102(6): 663 - 669. [Abstract] [Full Text] [PDF]

				N. Frey, W. M. Franz, K. Gloeckner, M. Degenhardt, M. Muller, O. Muller, H. Merz, and H. A. Katus Transgenic rat hearts expressing a human cardiac troponin T deletion reveal diastolic dysfunction and ventricular arrhythmias Cardiovasc Res, August 1, 2000; 47(2): 254 - 264. [Abstract] [Full Text] [PDF]

				R.C. Saumarez and A.A. Grace Paced ventricular electrogram fractionation and sudden death in hypertrophic cardiomyopathy and other non-coronary heart diseases Cardiovasc Res, July 1, 2000; 47(1): 11 - 22. [Full Text] [PDF]

				C Wren, J J O'Sullivan, and C Wright Sudden death in children and adolescents Heart, April 1, 2000; 83(4): 410 - 413. [Abstract] [Full Text]

				J. A. Moolman, S. Reith, K. Uhl, S. Bailey, M. Gautel, B. Jeschke, C. Fischer, J. Ochs, W. J. McKenna, H. Klues, et al. A Newly Created Splice Donor Site in Exon 25 of the MyBP-C Gene Is Responsible for Inherited Hypertrophic Cardiomyopathy With Incomplete Disease Penetrance Circulation, March 28, 2000; 101(12): 1396 - 1402. [Abstract] [Full Text] [PDF]

				P. A. Doevendans Hypertrophic Cardiomyopathy : Do We Have the Algorithm for Life and Death? Circulation, March 21, 2000; 101(11): 1224 - 1226. [Full Text] [PDF]

				D. Szczesna, R. Zhang, J. Zhao, M. Jones, G. Guzman, and J. D. Potter Altered Regulation of Cardiac Muscle Contraction by Troponin T Mutations That Cause Familial Hypertrophic Cardiomyopathy J. Biol. Chem., January 7, 2000; 275(1): 624 - 630. [Abstract] [Full Text] [PDF]

				A Varnava, C Baboonian, F Davison, L de Cruz, P M Elliott, M J Davies, and W J McKenna A new mutation of the cardiac troponin T gene causing familial hypertrophic cardiomyopathy without left ventricular hypertrophy Heart, November 1, 1999; 82(5): 621 - 624. [Abstract] [Full Text]

				C. S. Redwood, J. C. Moolman-Smook, and H. Watkins Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy Cardiovasc Res, October 1, 1999; 44(1): 20 - 36. [Abstract] [Full Text] [PDF]

				F. Yanaga, S. Morimoto, and I. Ohtsuki Ca2+ Sensitization and Potentiation of the Maximum Level of Myofibrillar ATPase Activity Caused by Mutations of Troponin T Found in Familial Hypertrophic Cardiomyopathy J. Biol. Chem., March 26, 1999; 274(13): 8806 - 8812. [Abstract] [Full Text] [PDF]

				A. Hinkle, A. Goranson, C. A. Butters, and L. S. Tobacman Roles for the Troponin Tail Domain in Thin Filament Assembly and Regulation. A DELETIONAL STUDY OF CARDIAC TROPONIN T J. Biol. Chem., March 12, 1999; 274(11): 7157 - 7164. [Abstract] [Full Text] [PDF]

				S. G. Priori, J. Barhanin, R. N. W. Hauer, W. Haverkamp, H. J. Jongsma, A. G. Kleber, W. J. McKenna, D. M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Parts I and II Circulation, February 2, 1999; 99(4): 518 - 528. [Abstract] [Full Text] [PDF]

				S.G. Priori, J. Barhanin, R.N.W. Hauer, W. Haverkamp, H.J. Jongsma, A.G. Kleber, W.J. McKenna, D.M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management Eur. Heart J., February 1, 1999; 20(3): 174 - 195. [PDF]

				H. L. Sweeney, H. S. Feng, Z. Yang, and H. Watkins Functional analyses of troponin T mutations that cause hypertrophic cardiomyopathy: Insights into disease pathogenesis and troponin function PNAS, November 24, 1998; 95(24): 14406 - 14410. [Abstract] [Full Text] [PDF]

				B. J. Maron, J. H. Moller, C. E. Seidman, G. M. Vincent, H. C. Dietz, A. J. Moss, J. A. Towbin, H. M. Sondheimer, R. E. Pyeritz, G. McGee, et al. Impact of Laboratory Molecular Diagnosis on Contemporary Diagnostic Criteria for Genetically Transmitted Cardiovascular Diseases: Hypertrophic Cardiomyopathy, Long-QT Syndrome, and Marfan Syndrome : A Statement for Healthcare Professionals From the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association Circulation, October 6, 1998; 98(14): 1460 - 1471. [Full Text] [PDF]

				G. Bonne, L. Carrier, P. Richard, B. Hainque, and K. Schwartz Familial Hypertrophic Cardiomyopathy : From Mutations to Functional Defects Circ. Res., September 21, 1998; 83(6): 580 - 593. [Abstract] [Full Text] [PDF]

				R. Anan, H. Shono, A. Kisanuki, S. Arima, S. Nakao, and H. Tanaka Patients With Familial Hypertrophic Cardiomyopathy Caused by a Phe110Ile Missense Mutation in the Cardiac Troponin T Gene Have Variable Cardiac Morphologies and a Favorable Prognosis Circulation, August 4, 1998; 98(5): 391 - 397. [Abstract] [Full Text] [PDF]

				P. Charron, O. Dubourg, M. Desnos, M. Bennaceur, L. Carrier, A.-C. Camproux, R. Isnard, A. Hagege, J. M. Langlard, G. Bonne, et al. Clinical Features and Prognostic Implications of Familial Hypertrophic Cardiomyopathy Related to the Cardiac Myosin-Binding Protein C Gene Circulation, June 9, 1998; 97(22): 2230 - 2236. [Abstract] [Full Text] [PDF]

				B. C. Knollmann, S. A. Blatt, K. Horton, F. de Freitas, T. Miller, M. Bell, P. R. Housmans, N. J. Weissman, M. Morad, and J. D. Potter Inotropic Stimulation Induces Cardiac Dysfunction in Transgenic Mice Expressing a Troponin T (I79N) Mutation Linked to Familial Hypertrophic Cardiomyopathy J. Biol. Chem., March 23, 2001; 276(13): 10039 - 10048. [Abstract] [Full Text] [PDF]