DILATED CARDIOMYOPATHY: EDITORIAL COMMENT
Severe disease expression of cardiac troponin C and T mutations in patients with idiopathic dilated cardiomyopathy
Jens Mogensen, MD, PhD*,*,
Ross T. Murphy, MD*,
Tony Shaw, PhD*,
Ajay Bahl, MD*,
Charles Redwood, PhD ,
Hugh Watkins, MD, PhD,
Margaret Burke, MD ,
Perry M. Elliott, MD* and
William J. McKenna, MD*
* Department of Cardiological Sciences, St. George's Hospital Medical School, London, United Kingdom
Harefield Hospital, Middlesex, United Kingdom
John Radcliffe Hospital, Oxford, United Kingdom
Manuscript received March 22, 2004;
revised manuscript received July 29, 2004,
accepted August 3, 2004.
* Reprint requests and correspondence: Dr. Jens Mogensen, Department of Cardiology, Skejby University Hospital, Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark (Email: jens.mogensen{at}dadlnet.dk).
OBJECTIVES: We performed genetic investigations of cardiac troponin T (TNNT2) and troponin C (TNNC1) in 235 consecutive patients with idiopathic dilated cardiomyopathy (DCM) to evaluate prevalence of mutations and associated disease expression in affected families.
BACKGROUND: Recently, mutations in sarcomeric genes have been reported in DCM. However, the prevalence, penetrance, and clinical significance of sarcomere gene mutations in large consecutive cohorts of DCM patients are poorly defined.
METHODS: Mutation detection was performed by fluorescent SSCP/DHPLC analysis and direct sequencing. The functional effects of mutations on interactions within the troponin complex were assessed by a two-hybrid luciferase assay.
RESULTS: A total of 43% (102 of 235) of the study cohort had familial DCM. One TNNC1 and four TNNT2 (three novel) mutations were identified in one and four families, respectively. The prevalence of TNNC1/TNNT2 mutations in familial DCM was 5% with a penetrance of 100%. A total of 21 mutation carriers were identified; 6 underwent cardiac transplantation, 5 died of heart failure, and 4 died suddenly at a mean age of 29 years, while 6 remained stable on medication.Functional studies showed significant impairment of mutated troponin interaction compared with wild-type control, indicating an altered regulation of myocardial contractility.
CONCLUSIONS: Cardiac troponin C was identified as a novel DCM gene. The disease expression associated with TNNC1 and TNNT2 mutations was severe with complete penetrance. The data suggest that mutation analysis of the troponin complex in DCM patients may prove valuable in early identification of individuals with an adverse prognosis and a high risk of premature death. This may lead to improved management and survival.
|
Abbreviations and Acronyms
| | DCM = dilated cardiomyopathy | | DHPLC = denaturing high performance liquid chromatography | | F-SSCP = fluorescent SSCP | | LVEDD = left ventricular end-diastolic dimension | | LVESD = left ventricular end-systolic dimension | | TNNC1 = cardiac troponin C | | TNNI3 = cardiac troponin I | | TNNT2 = cardiac troponin T |
|
This article has been cited by other articles:
|
|
|
|
 
D.-Y. Zhan, S. Morimoto, C.-K. Du, Y.-Y. Wang, Q.-W. Lu, A. Tanaka, T. Ide, Y. Miwa, F. Takahashi-Yanaga, and T. Sasaguri
Therapeutic effect of {beta}-adrenoceptor blockers using a mouse model of dilated cardiomyopathy with a troponin mutation
Cardiovasc Res,
June 17, 2009;
(2009)
cvp168v2.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Dweck, N. Hus, and J. D. Potter
Challenging Current Paradigms Related to Cardiomyopathies: ARE CHANGES IN THE Ca2+ SENSITIVITY OF MYOFILAMENTS CONTAINING CARDIAC TROPONIN C MUTATIONS (G159D AND L29Q) GOOD PREDICTORS OF THE PHENOTYPIC OUTCOMES?
J. Biol. Chem.,
November 28, 2008;
283(48):
33119 - 33128.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger
Designing Heart Performance by Gene Transfer
Physiol Rev,
October 1, 2008;
88(4):
1567 - 1651.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Morimoto
Sarcomeric proteins and inherited cardiomyopathies
Cardiovasc Res,
March 1, 2008;
77(4):
659 - 666.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-J. Dong, J. Xing, Y. Ouyang, J. An, and H. C. Cheung
Structural Kinetics of Cardiac Troponin C Mutants Linked to Familial Hypertrophic and Dilated Cardiomyopathy in Troponin Complexes
J. Biol. Chem.,
February 8, 2008;
283(6):
3424 - 3432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Robinson, P. J. Griffiths, H. Watkins, and C. S. Redwood
Dilated and Hypertrophic Cardiomyopathy Mutations in Troponin and {alpha}-Tropomyosin Have Opposing Effects on the Calcium Affinity of Cardiac Thin Filaments
Circ. Res.,
December 7, 2007;
101(12):
1266 - 1273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-K. Du, S. Morimoto, K. Nishii, R. Minakami, M. Ohta, N. Tadano, Q.-W. Lu, Y.-Y. Wang, D.-Y. Zhan, M. Mochizuki, et al.
Knock-In Mouse Model of Dilated Cardiomyopathy Caused by Troponin Mutation
Circ. Res.,
July 20, 2007;
101(2):
185 - 194.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Biesiadecki, T. Kobayashi, J. S. Walker, R. John Solaro, and P. P. de Tombe
The Troponin C G159D Mutation Blunts Myofilament Desensitization Induced by Troponin I Ser23/24 Phosphorylation
Circ. Res.,
May 25, 2007;
100(10):
1486 - 1493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mirza, P. Robinson, E. Kremneva, O. Copeland, O. Nikolaeva, H. Watkins, D. Levitsky, C. Redwood, M. EL-Mezgueldi, and S. Marston
The Effect of Mutations in {alpha}-Tropomyosin (E40K and E54K) That Cause Familial Dilated Cardiomyopathy on the Regulatory Mechanism of Cardiac Muscle Thin Filaments
J. Biol. Chem.,
May 4, 2007;
282(18):
13487 - 13497.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Donahue, D. A. Marchuk, and H. A. Rockman
Redefining Heart Failure: The Utility of Genomics
J. Am. Coll. Cardiol.,
October 3, 2006;
48(7):
1289 - 1298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Adamcova, M. Sterba, T. Simunek, A. Potacova, O. Popelova, and V. Gersl
Myocardial regulatory proteins and heart failure
Eur J Heart Fail,
June 1, 2006;
8(4):
333 - 342.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Mirza, S. Marston, R. Willott, C. Ashley, J. Mogensen, W. McKenna, P. Robinson, C. Redwood, and H. Watkins
Dilated Cardiomyopathy Mutations in Three Thin Filament Regulatory Proteins Result in a Common Functional Phenotype
J. Biol. Chem.,
August 5, 2005;
280(31):
28498 - 28506.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. J. Osterziel and A. Perrot
Dilated cardiomyopathy: more genes means more phenotypes
Eur. Heart J.,
April 2, 2005;
26(8):
751 - 754.
[Full Text]
[PDF]
|
|
|
|
