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Background <p>Dilated cardiomyopathy (DCM) is a genetic cardiac disorder characterized by ventricular dilation and systolic dysfunction. Mutations in calcium-handling genes such as <i>JPH2</i>, which plays a critical role in maintaining cardiac dyad integrity, have been associated with DCM. Although more than 20 <i>JPH2</i> variants have been reported, most lack functional validation. This study investigates the ClinVar-listed <i>JPH2</i> p.R160H variant and provides initial cellular evidence related to its pathogenic potential, based on genetic data and stress-response assays.</p> Methods <p>A 33-year-old male with severe DCM (LVEF 26%) and asymptomatic parents underwent trio-based whole-exome sequencing (WES). Rare variants were filtered (MAF &lt; 0.01) and prioritized using ACMG guidelines. The <i>JPH2</i> p.R160H variant was cloned and transfected into AC16 cardiomyocytes. Protein expression levels of MYH7, α-SMA, and TGF-β were assessed by Western blotting. Evolutionary conservation of R160 was evaluated using ClustalX.</p> Results <p>Trio-based WES identified a de novo <i>JPH2</i> p.R160H variant absent in both parents and population controls. AC16 cells expressing the mutant construct showed increased levels of myocardial stress markers (MYH7, α-SMA, and TGF-β). JPH2 protein expression was also elevated, indicating possible dysregulation of protein turnover or stability. Evolutionary analysis confirmed that R160 is highly conserved across species. According to ACMG criteria (PS2, PS3, PM2, PP4), the variant was classified as pathogenic.</p> Conclusion <p>This study provides preliminary cellular evidence supporting the pathogenic potential of the <i>JPH2</i> p.R160H variant, while the direct effects on calcium handling and dyad integrity remain unknown.The combined genetic and cellular data contribute to more accurate variant classification and support the inclusion of <i>JPH2</i> in cardiomyopathy genetic screening. Further mechanistic studies—particularly those assessing calcium handling—are warranted to elucidate the broader functional impact of this variant.</p>

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Functional characterization of a novel JPH2 variant (p.R160H) associated with dilated cardiomyopathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月20日

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  • Kailu Jiao,
  • Ke Gong,
  • Yong Luo,
  • RuiLin Liu,
  • Lei Wang,
  • Yao Yao,
  • Li Xie

摘要

Background

Dilated cardiomyopathy (DCM) is a genetic cardiac disorder characterized by ventricular dilation and systolic dysfunction. Mutations in calcium-handling genes such as JPH2, which plays a critical role in maintaining cardiac dyad integrity, have been associated with DCM. Although more than 20 JPH2 variants have been reported, most lack functional validation. This study investigates the ClinVar-listed JPH2 p.R160H variant and provides initial cellular evidence related to its pathogenic potential, based on genetic data and stress-response assays.

Methods

A 33-year-old male with severe DCM (LVEF 26%) and asymptomatic parents underwent trio-based whole-exome sequencing (WES). Rare variants were filtered (MAF < 0.01) and prioritized using ACMG guidelines. The JPH2 p.R160H variant was cloned and transfected into AC16 cardiomyocytes. Protein expression levels of MYH7, α-SMA, and TGF-β were assessed by Western blotting. Evolutionary conservation of R160 was evaluated using ClustalX.

Results

Trio-based WES identified a de novo JPH2 p.R160H variant absent in both parents and population controls. AC16 cells expressing the mutant construct showed increased levels of myocardial stress markers (MYH7, α-SMA, and TGF-β). JPH2 protein expression was also elevated, indicating possible dysregulation of protein turnover or stability. Evolutionary analysis confirmed that R160 is highly conserved across species. According to ACMG criteria (PS2, PS3, PM2, PP4), the variant was classified as pathogenic.

Conclusion

This study provides preliminary cellular evidence supporting the pathogenic potential of the JPH2 p.R160H variant, while the direct effects on calcium handling and dyad integrity remain unknown.The combined genetic and cellular data contribute to more accurate variant classification and support the inclusion of JPH2 in cardiomyopathy genetic screening. Further mechanistic studies—particularly those assessing calcium handling—are warranted to elucidate the broader functional impact of this variant.