Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy.
OBJECTIVE
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.
Hayashi
Takeharu
T
Department of Molecular Pathogenesis, Medical Research Institute, and Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.
Arimura
Takuro
T
Itoh-Satoh
Manatsu
M
Ueda
Kazuo
K
Hohda
Shigeru
S
Inagaki
Natsuko
N
Takahashi
Megumi
M
Hori
Hisae
H
Yasunami
Michio
M
Nishi
Hirofumi
H
Koga
Yoshinori
Y
Nakamura
Hiroshi
H
Matsuzaki
Masunori
M
Choi
Bo Yoon
BY
Bae
Sung Won
SW
You
Cheol Woon
CW
Han
Kyung Hoon
KH
Park
Jeong Euy
JE
Knöll
Ralph
R
Hoshijima
Masahiko
M
Chien
Kenneth R
KR
Kimura
Akinori
A
D044466:Asian People / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D064211:Connectin; D017931:DNA Primers; D005978:Glutathione; D006801:Humans; D007723:Korea; D060588:LIM Domain Proteins; D009124:Muscle Proteins / Q000235:genetics*; D019683:Penetrance; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics; D016415:Sequence Alignment; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D064211:Connectin; D017931:DNA Primers; D005978:Glutathione; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D011494:Protein Kinases; D000099163:Myosin Binding Protein C; C577292:TCAP protein, human; C577285:TTN protein, human; C090114:cysteine and glycine-rich protein 3