Dilated Cardiomyopathy-Associated FHOD3 Variant Impairs the Ability to Induce Activation of Transcription Factor Serum Response Factor

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Author(s)

    • ARIMURA Takuro
    • Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University
    • TAKEYA Ryu
    • Department of Biochemistry, Kyushu University Graduate School of Medical Sciences
    • ISHIKAWA Taisuke
    • Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University
    • YAMANO Tetsuhiro
    • Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine
    • MATSUO Akiko
    • Division of Cardiovascular Medicine, Japanese Red Cross Kyoto Daini Hospital
    • SUMIMOTO Hideki
    • Department of Biochemistry, Kyushu University Graduate School of Medical Sciences
    • KIMURA Akinori
    • Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University

Abstract

<b><i>Background:</i></b> Dilated cardiomyopathy (DCM) is characterized by a dilated left ventricular cavity with systolic dysfunction manifested by heart failure. It has been revealed that mutations in genes for cytoskeleton or sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in far less than half of patients with a family history, indicating that there should be other disease genes for DCM. Formin homology 2 domain containing 3 (FHOD3) is a sarcomeric protein expressed in the heart that plays an essential role in sarcomere organization during myofibrillogenesis. The purpose of this study was to explore a possible novel disease gene for DCM. <b><i>Methods and Results:</i></b> We analyzed 48 Japanese familial DCM patients for mutations in <i>FHOD3</i>, and a missense variant, Tyr1249Asn, which was predicted to modify the 3D structure and damage protein function, was found in a case with adult-onset DCM. Functional studies revealed that the DCM-associated mutation significantly reduced the ability to induce actin dynamics-dependent activation of serum response factor, although no remarkable change in the cellular localization was induced in neonatal rat cardiomyocytes transfected with a mutant construct of <i>FHOD3</i>. <b><i>Conclusions:</i></b> The DCM-associated <i>FHOD3</i> variant may cause DCM by interfering with actin filament assembly.  (<i>Circ J</i> 2013; <b>77:</b> 2990–2996)<br>

Journal

  • Circulation Journal

    Circulation Journal 77(12), 2990-2996, 2013-11-25

    The Japanese Circulation Society

References:  26

Cited by:  1

Codes

  • NII Article ID (NAID)
    10031203585
  • NII NACSIS-CAT ID (NCID)
    AA11591968
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    13469843
  • Data Source
    CJP  CJPref  J-STAGE 
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