Abstract
Hypertrophic cardiomyopathy and dilated cardiomyopathy are two major clinical phenotypes of "idiopathic" cardiomyopathy. Recent molecular genetic analyses have now revealed that "idiopathic" cardiomyopathy is caused by mutations in genes for sarcomere components. We have recently reported several mutations in titin/connectin gene found in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy. A hypertrophic cardiomyopathy-associated titin/connectin mutation (Arg740Leu) was found to increase the binding to actinin, while other dilated cardiomyopathy-associated titin/connectin mutations (Ala743Val and Val54Met) decreased the binding to actinin and Tcap/telethonin, respectively. We also reported several other mutations in the N2-B region of titin/connectin found in hypertrophic cardiomyopathy and dilated cardiomyopathy. Since the N2-B region expresses only in the heart, it was speculated that functional alterations due to the mutations cause cardiomyopathies. In this study, we investigated the functional changes caused by the N2-B region mutations by using yeast-two-hybrid assays. It was revealed that a hypertrophic cardiomyopathy-associated mutation (Ser3799Tyr) increased the binding to FHL2 protein, whereas a dilated cardiomyopathy- associated mutation (Gln4053ter) decreased the binding. In addition, another TTN mutation (Arg25618Gln) at the is2 region was found in familial DCM. Because FHL2 protein is known to tether metabolic enzymes to N2-B and is2 regions of titin/connectin, these observations suggest that altered recruitment of metabolic enzymes to the sarcomere may play a role in the pathogenesis of cardiomyopathies.
| Original language | English |
|---|---|
| Pages (from-to) | 367-374 |
| Number of pages | 8 |
| Journal | Journal of Muscle Research and Cell Motility |
| Volume | 26 |
| Issue number | 6-8 |
| DOIs | |
| Publication status | Published - Dec 2005 |
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ASJC Scopus subject areas
- Physiology
- Clinical Biochemistry
- Endocrinology
- Cell Biology
Cite this
Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy. / Matsumoto, Yuji; Hayashi, Takeharu; Inagaki, Natsuko; Takahashi, Megumi; Hiroi, Shitoshi; Nakamura, Takeyuki; Arimura, Takuro; Nakamura, Kazufumi; Ashizawa, Naoto; Yasunami, Michio; Ohe, Toru; Yano, Katsusuke; Kimura, Akinori.
In: Journal of Muscle Research and Cell Motility, Vol. 26, No. 6-8, 12.2005, p. 367-374.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy
AU - Matsumoto, Yuji
AU - Hayashi, Takeharu
AU - Inagaki, Natsuko
AU - Takahashi, Megumi
AU - Hiroi, Shitoshi
AU - Nakamura, Takeyuki
AU - Arimura, Takuro
AU - Nakamura, Kazufumi
AU - Ashizawa, Naoto
AU - Yasunami, Michio
AU - Ohe, Toru
AU - Yano, Katsusuke
AU - Kimura, Akinori
PY - 2005/12
Y1 - 2005/12
N2 - Hypertrophic cardiomyopathy and dilated cardiomyopathy are two major clinical phenotypes of "idiopathic" cardiomyopathy. Recent molecular genetic analyses have now revealed that "idiopathic" cardiomyopathy is caused by mutations in genes for sarcomere components. We have recently reported several mutations in titin/connectin gene found in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy. A hypertrophic cardiomyopathy-associated titin/connectin mutation (Arg740Leu) was found to increase the binding to actinin, while other dilated cardiomyopathy-associated titin/connectin mutations (Ala743Val and Val54Met) decreased the binding to actinin and Tcap/telethonin, respectively. We also reported several other mutations in the N2-B region of titin/connectin found in hypertrophic cardiomyopathy and dilated cardiomyopathy. Since the N2-B region expresses only in the heart, it was speculated that functional alterations due to the mutations cause cardiomyopathies. In this study, we investigated the functional changes caused by the N2-B region mutations by using yeast-two-hybrid assays. It was revealed that a hypertrophic cardiomyopathy-associated mutation (Ser3799Tyr) increased the binding to FHL2 protein, whereas a dilated cardiomyopathy- associated mutation (Gln4053ter) decreased the binding. In addition, another TTN mutation (Arg25618Gln) at the is2 region was found in familial DCM. Because FHL2 protein is known to tether metabolic enzymes to N2-B and is2 regions of titin/connectin, these observations suggest that altered recruitment of metabolic enzymes to the sarcomere may play a role in the pathogenesis of cardiomyopathies.
AB - Hypertrophic cardiomyopathy and dilated cardiomyopathy are two major clinical phenotypes of "idiopathic" cardiomyopathy. Recent molecular genetic analyses have now revealed that "idiopathic" cardiomyopathy is caused by mutations in genes for sarcomere components. We have recently reported several mutations in titin/connectin gene found in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy. A hypertrophic cardiomyopathy-associated titin/connectin mutation (Arg740Leu) was found to increase the binding to actinin, while other dilated cardiomyopathy-associated titin/connectin mutations (Ala743Val and Val54Met) decreased the binding to actinin and Tcap/telethonin, respectively. We also reported several other mutations in the N2-B region of titin/connectin found in hypertrophic cardiomyopathy and dilated cardiomyopathy. Since the N2-B region expresses only in the heart, it was speculated that functional alterations due to the mutations cause cardiomyopathies. In this study, we investigated the functional changes caused by the N2-B region mutations by using yeast-two-hybrid assays. It was revealed that a hypertrophic cardiomyopathy-associated mutation (Ser3799Tyr) increased the binding to FHL2 protein, whereas a dilated cardiomyopathy- associated mutation (Gln4053ter) decreased the binding. In addition, another TTN mutation (Arg25618Gln) at the is2 region was found in familial DCM. Because FHL2 protein is known to tether metabolic enzymes to N2-B and is2 regions of titin/connectin, these observations suggest that altered recruitment of metabolic enzymes to the sarcomere may play a role in the pathogenesis of cardiomyopathies.
UR - http://www.scopus.com/inward/record.url?scp=33745698393&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33745698393&partnerID=8YFLogxK
U2 - 10.1007/s10974-005-9018-5
DO - 10.1007/s10974-005-9018-5
M3 - Article
C2 - 16465475
AN - SCOPUS:33745698393
VL - 26
SP - 367
EP - 374
JO - Journal of Muscle Research and Cell Motility
JF - Journal of Muscle Research and Cell Motility
SN - 0142-4319
IS - 6-8
ER -