Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.

Abstract

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.

• Authors: Takeharu Hayashi, Takuro Arimura, Manatsu Itoh-Satoh, Kazuo Ueda, Shigeru Hohda, Natsuko Inagaki, Megumi Takahashi, Hisae Hori, Michio Yasunami, Hirofumi Nishi, Yoshinori Koga, Hiroshi Nakamura, Masunori Matsuzaki, Bo Yoon Choi, Sung Won Bae, Cheol Woon You, Kyung Hoon Han, Jeong Euy Park, Ralph Knöll, Masahiko Hoshijima, Kenneth R Chien, Akinori Kimura
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 44 Issue 11 Pg. 2192-201 (Dec 07 2004) ISSN: 0735-1097 [Print] United States
• PMID: 15582318 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Connectin
• DNA Primers
• LIM Domain Proteins
• Muscle Proteins
• TCAP protein, human
• TTN protein, human
• cysteine and glycine-rich protein 3
• myosin-binding protein C
• Protein Kinases
• Glutathione

Topics

• Asian People (genetics)
• Cardiomyopathy, Dilated (genetics)
• Cardiomyopathy, Hypertrophic (genetics)
• Carrier Proteins (genetics)
• Connectin
• DNA Primers
• Glutathione
• Humans
• Korea
• LIM Domain Proteins
• Muscle Proteins (genetics)
• Penetrance
• Protein Binding
• Protein Kinases (genetics)
• Sequence Alignment