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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

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