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TPM1-p.E181K mutation suppresses CaMKII/HDAC4 signaling pathway leading to pediatric restrictive cardiomyopathy

Jia Fu1, Jing Zhang1, Youxian Zhang2

  • 1Department of Cardiology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Frontiers in Genetics
|January 22, 2026
PubMed

Insights

A novel TPM1 mutation (p.Glu181Lys) is linked to restrictive cardiomyopathy (RCM). This mutation disrupts calcium signaling and CaMKII/HDAC4 phosphorylation, leading to abnormal heart muscle contractility and RCM pathogenesis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Genetic Pathology

Background:

  • Restrictive cardiomyopathy (RCM) is a severe heart condition.
  • The role of TPM1 mutations in sporadic RCM is not well understood.
  • This study investigates a specific TPM1 mutation (p.Glu181Lys) in RCM.

Purpose of the Study:

  • To determine the pathogenicity of the TPM1 p.Glu181Lys mutation.
  • To classify the mutation's ACMG pathogenicity.
  • To elucidate the molecular mechanisms underlying its association with sporadic RCM.

Main Methods:

  • Protein 3D modeling to predict structural changes.
  • Cellular assays using AC16 cardiomyocyte cell lines with wild-type and mutant TPM1.
  • Quantitative PCR, Western blotting, calcium transient analysis, and F-actin staining.
  • Evaluation of CaMKII/HDAC4 pathway phosphorylation and troponin activity.

Main Results:

  • The TPM1 p.Glu181Lys mutation alters protein structure but not overall expression.
  • Intracellular calcium transients and CaMKII/HDAC4 phosphorylation are significantly suppressed.
  • Troponin activity is impaired, leading to abnormal cardiomyocyte contractility.

Conclusions:

  • A novel association between TPM1 p.Glu181Lys and sporadic RCM is established.
  • Pathogenesis involves calcium dyshomeostasis, suppressed CaMKII/HDAC4 phosphorylation, and sarcomere disruption.
  • The CaMKII/HDAC4 signaling axis presents a potential therapeutic target for RCM.
Abstract

Keywords:
CaMKII/HDAC4TPM1-p.E181Kmolecular mechanismspediatric cardiologyrestrictive cardiomyopathy

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