Dilated cardiomyopathy-associated FHOD3 variant impairs the ability to induce activation of transcription factor serum response factor

Takuro Arimura, Ryu Takeya, Taisuke Ishikawa, Tetsuhiro Yamano, Akiko Matsuo, Tetsuya Tatsumi, Tetsuya Nomura, Hideki Sumimoto, Akinori Kimura

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Background: 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. Methods and Results: We analyzed 48 Japanese familial DCM patients for mutations in FHOD3, 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 FHOD3. Conclusions: The DCM-associated FHOD3 variant may cause DCM by interfering with actin filament assembly.

Original languageEnglish
Pages (from-to)2990-2996
Number of pages7
JournalCirculation Journal
Volume77
Issue number12
DOIs
Publication statusPublished - 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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