Article Text

Download PDFPDF
Original research
Association between SCN5A R225Q variant and dilated cardiomyopathy: potential role of intracellular pH and WNT/β-catenin pathway
  1. Jingjing Hu1,2,
  2. Kun Yang1,
  3. Yongchao Zhao1,
  4. Zilun Wei1,
  5. Lebing Yang3,
  6. Rifeng Gao1,
  7. Yonghui Wu3,
  8. Lei Xu1,
  9. Sujuan Xu1,
  10. Kai Hu1,
  11. Aijun Sun1,
  12. Junbo Ge1
  1. 1 Cardiology Department, Zhong Shan Hospital, Shanghai, China
  2. 2 Cardiology Department, The First Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang Province, China, China
  3. 3 Wen Zhou Yi Ke Da Xue, Wenzhou, Zhejiang, China
  1. Correspondence to Dr Aijun Sun, Zhongshan, Zhongshan Hospital Fudan University, Shanghai, Shanghai, China; sun.aijun{at}


Background The SCN5A variant is a common cause of familial dilated cardiomyopathy (DCM). We previously reported a SCN5A variant (c.674G>A), located in the high-risk S4 segment of domain I (DI-S4) region in patients with idiopathic DCM and R225Q knockin (p.R225Q) mice carrying the c.674G>A variant exhibited prolonged baseline PR intervals without DCM phenotypes. In this study, we explored the association and mechanism between R225Q variant and DCM phenotype.

Methods Prevalence of DI-S4 variant was compared between patients with idiopathic DCM and the control participants. R225Q knockin and wild-type (WT) mice were subjected to doxorubicin (DOX), D-galactose (D-gal) or D-gal combined with DOX.

Results Clinical data suggested that the prevalence of DI-S4 variant was higher in DCM group than in the control group (4/90 (4.4%) vs 3/1339 (0.2%), p<0.001). Cardiomyocytes from R225Q knockin mice treated with D-gal and DOX exhibited more significant hypertrophic phenotype and weaker contraction/dilation function and an increased level of apoptosis as compared with WT mice. Mechanistically, we found that R225Q variant could increase intracellular pH and further induce the activation of the WNT/β-catenin pathway as well as the overexpression of pro-hypertrophic and pro-apoptotic targets. WNT-C59 inhibitor improved cardiac function in the R225Q knockin mice treated with D-gal and DOX.

Conclusion Our results suggest that R225Q variant is associated with increased susceptibility to DCM. Ageing could enhance this process via activating WNT/β-catenin signaling in response to increased intracellular pH. Antagonising the WNT/β-catenin pathway might be a potential therapeutic strategy for mitigating R225Q variant-related DCM pathogenesis.

  • cardiovascular diseases
  • gene expression
  • pathology

Data availability statement

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

View Full Text


  • JH, KY, YZ and ZW contributed equally.

  • Contributors AS, JG and KH conceived and designed the study. JH, KY, RG and YZ performed most of the experiments and wrote the manuscript. ZW and YW contributed to the figures. LY, SX and LX analysed the data. AS and KH revised the manuscript.

  • Funding This study was supported by grants to AS from the National Key R&D Program of China (2021YFC2701103) and the National Science Fund for Distinguished Young Scholars (81725002) and a grant to LX from the National Natural Science Fundation of China (82070242).

  • Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.