CARDIOMYOPATHY
Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy
Takeharu Hayashi, MD, PhD*,
Takuro Arimura, DVM, PhD*,
Manatsu Itoh-Satoh, MD, PhD*,
Kazuo Ueda, MD*,
Shigeru Hohda, MD, PhD*,
Natsuko Inagaki, MD*,
Megumi Takahashi, MS*,
Hisae Hori, PhD*,
Michio Yasunami, MD, PhD*,
Hirofumi Nishi, MD, PhD ,
Yoshinori Koga, MD, PhD,
Hiroshi Nakamura, MD, PhD ,
Masunori Matsuzaki, MD, PhD,
Bo Yoon Choi, MS ,
Sung Won Bae, PhD,
Cheol Woon You, MD,
Kyung Hoon Han, MD||,
Jeong Euy Park, MD,
Ralph Knöll, MD, PhD¶,
Masahiko Hoshijima, MD, PhD¶,
Kenneth R. Chien, MD, PhD¶ and
Akinori Kimura, MD, PhD*,*
* Department of Molecular Pathogenesis, Medical Research Institute, and Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan
Department of Cardiology, Kurume University Medical School, Kurume, Japan
Second Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Japan
Department of Cardiovascular Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
|| Cardiology Division, Han Kook General Hospital, Jeju, Korea
¶ Institute of Molecular Medicine, Departments of Medicine, Psychiatry, and Bioengineering, University of California at San Diego, La Jolla, California
Manuscript received May 19, 2004;
revised manuscript received July 26, 2004,
accepted August 25, 2004.
* Reprint requests and correspondence: Dr. Akinori Kimura, Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan (Email: akitis{at}mri.tmd.ac.jp).
OBJECTIVES: We sought to explore the relationship between a Tcap gene (TCAP) abnormality and cardiomyopathy.
BACKGROUND: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cause severe heart failure and sudden death. Recent genetic investigations have revealed that mutations of genes encoding Z-disc components, including titin and muscle LIM protein (MLP), are the primary cause of both HCM and DCM. The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc.
METHODS: The TCAP was analyzed in 346 patients with HCM (236 familial and 110 sporadic cases) and 136 patients with DCM (34 familial and 102 sporadic cases). Two different in vitro qualitative assays—yeast two-hybrid and glutathion S-transferase pull-down competition—were performed in order to investigate functional changes in Tcap's interaction with MLP, titin, and calsarcin-1 caused by the identified mutations and a reported DCM-associated mutation, R87Q.
RESULTS: Two TCAP mutations, T137I and R153H, were found in patients with HCM, and another TCAP mutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1.
CONCLUSIONS: These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components.
|
Abbreviations and Acronyms
| | CS-1 = calsarcin-1 | | DCM = dilated cardiomyopathy | | GST = glutathion S-transferase | | HCM = hypertrophic cardiomyopathy | | LV = left ventricle/ventricular | | MLP = muscle LIM protein | | PCR = polymerase chain reaction | | RT = reverse transcription | | SSCP = single-strand conformation polymorphism | | Thio = thioredoxin | | WT = wild-type | | Y2H = yeast two-hybrid |
|
This article has been cited by other articles:
|
|
|
|
 
A. Borbely, I. Falcao-Pires, L. van Heerebeek, N. Hamdani, I. Edes, C. Gavina, A. F. Leite-Moreira, J. G.F. Bronzwaer, Z. Papp, J. van der Velden, et al.
Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium
Circ. Res.,
March 27, 2009;
104(6):
780 - 786.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. A. Linke
Sense and stretchability: The role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction
Cardiovasc Res,
March 1, 2008;
77(4):
637 - 648.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Morimoto
Sarcomeric proteins and inherited cardiomyopathies
Cardiovasc Res,
March 1, 2008;
77(4):
659 - 666.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Mery, O. Taghli-Lamallem, K. A. Clark, M. C. Beckerle, X. Wu, K. Ocorr, and R. Bodmer
The Drosophila muscle LIM protein, Mlp84B, is essential for cardiac function
J. Exp. Biol.,
January 1, 2008;
211(1):
15 - 23.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Wiersma, P. Stabej, P. A. J. Leegwater, B. A. Van Oost, W. E. Ollier, and J. Dukes-McEwan
Evaluation of 15 Candidate Genes for Dilated Cardiomyopathy in the Newfoundland Dog
J. Hered.,
January 1, 2008;
99(1):
73 - 80.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Perrot, R. Dietz, and K. J. Osterziel
Is there a common genetic basis for all familial cardiomyopathies?
Eur J Heart Fail,
January 1, 2007;
9(1):
4 - 6.
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Hoshijima, R. Knoll, M. Pashmforoush, and K. R. Chien
Reversal of Calcium Cycling Defects in Advanced Heart Failure: Toward Molecular Therapy
J. Am. Coll. Cardiol.,
October 27, 2006;
48(9_Suppl_A):
A15 - A23.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Richard, E. Villard, P. Charron, and R. Isnard
The Genetic Bases of Cardiomyopathies
J. Am. Coll. Cardiol.,
October 27, 2006;
48(9_Suppl_A):
A79 - A89.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Musa, S. Meek, M. Gautel, D. Peddie, A. J. H. Smith, and M. Peckham
Targeted homozygous deletion of M-band titin in cardiomyocytes prevents sarcomere formation
J. Cell Sci.,
October 15, 2006;
119(20):
4322 - 4331.
[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. J. Ackerman, S. L. Van Driest, and M. Bos
Are Longitudinal, Natural History Studies the Next Step in Genotype-Phenotype Translational Genomics in Hypertrophic Cardiomyopathy?
J. Am. Coll. Cardiol.,
November 1, 2005;
46(9):
1744 - 1746.
[Full Text]
[PDF]
|
|
|
|
