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 Kimura

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67 Citations (Scopus)


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 languageEnglish
Pages (from-to)367-374
Number of pages8
JournalJournal of Muscle Research and Cell Motility
Issue number6-8
Publication statusPublished - Dec 2005

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cell Biology


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