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Journal of Muscle Research & Cell Motility

, Volume 26, Issue 6–8, pp 367–374 | Cite as

Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy

  • YUJI MATSUMOTO
  • TAKEHARU HAYASHI
  • NATSUKO INAGAKI
  • MEGUMI TAKAHASHI
  • SHITOSHI HIROI
  • TAKEYUKI NAKAMURA
  • TAKURO ARIMURA
  • KAZUFUMI NAKAMURA
  • NAOTO ASHIZAWA
  • MICHIO YASUNAMI
  • TORU OHE
  • KATSUSUKE YANO
  • AKINORI KIMURAEmail author
Article

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.

Keywords

Cardiomyopathy Dilate Cardiomyopathy Hypertrophic Cardiomyopathy Arg25618Gln Mutation Arg25618Gln Variation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations:

DCM

dilated cardiomyopathy

FHL2

four and half LIM protein 2

HCM

hypertrophic cardiomyopathy

MLP

muscle LIM protein

Tcap

titin-cap

Y2H

yeast two hybrid

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Notes

Acknowledgements

This work was supported in part by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan and a research grant from the Ministry of Health, Labor and Welfare, Japan and Mitsui Life Social Welfare Foundation. We are grateful to Drs H. Toshima, H. Nishi, Y. Koga, K. Matsuyama, T. Sakamoto, K. Kawai, K.␣Kawamura, R. Kusukawa, M. Nagano, Y.␣Nimura, R. Okada, T. Sugimoto, H. Tanaka, H. Yasuda, K. Fukuda, S. Ogawa, A. Matsumori, S. Sasayama, R. Nagai, and Y. Yazaki for their contributions in clinical evaluation and blood sampling from patients with HCM and DCM

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Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • YUJI MATSUMOTO
    • 1
    • 2
  • TAKEHARU HAYASHI
    • 1
  • NATSUKO INAGAKI
    • 1
  • MEGUMI TAKAHASHI
    • 1
  • SHITOSHI HIROI
    • 1
  • TAKEYUKI NAKAMURA
    • 1
  • TAKURO ARIMURA
    • 1
  • KAZUFUMI NAKAMURA
    • 3
  • NAOTO ASHIZAWA
    • 2
  • MICHIO YASUNAMI
    • 1
    • 4
  • TORU OHE
    • 3
  • KATSUSUKE YANO
    • 2
  • AKINORI KIMURA
    • 1
    • 4
    Email author
  1. 1.Department of Molecular Pathogenesis, Medical Research InstituteTokyo Medical and Dental UniversityTokyo Japan
  2. 2.Division of Cardiovascular Medicine, Graduate School of Biomedical SciencesNagasaki University School of MedicineNagasakiJapan
  3. 3.Department of Cardiovascular MedicineOkayama University School of MedicineOkayamaJapan
  4. 4.Laboratory of Genome Diversity, School of Biomedical ScienceTokyo Medical and Dental UniversityTokyoJapan

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