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Updated: May 20, 2026

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Variable cMyBP-C expression from cell to cell in a MYBPC3c.927-2 A>G hiPSC-CM model recapitulates HCM patient

Karina Ivaskevica1, Kathrin Kowalski1, Birgit Piep1

  • 1Institute of Molecular and Cell Physiology, Hannover Medical School (MHH), Hannover, Germany.

Stem Cell Research & Therapy
|May 19, 2026
PubMed

Insights

This study developed a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model for hypertrophic cardiomyopathy (HCM) caused by MYBPC3 mutations. The model replicates patient-specific cMyBP-C haploinsufficiency and myofibrillar disarray, aiding HCM research.

Area of Science:

  • Cardiovascular Research
  • Stem Cell Biology
  • Genetic Cardiology

Background:

  • Hypertrophic cardiomyopathy (HCM) is often linked to MYBPC3 gene mutations, leading to cardiac myosin binding protein C (cMyBP-C) haploinsufficiency.
  • Previous research indicated variable MYBPC3 transcription and cMyBP-C levels in HCM patient myocardium.

Purpose of the Study:

  • To create and validate a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model for MYBPC3-associated HCM.
  • To investigate if patient-specific MYBPC3 mutations induce comparable pathophysiological features in vitro during long-term culture.

Main Methods:

  • Generated hiPSC-CMs with a patient-specific MYBPC3 c.927-2 A>G splice-site mutation and an isogenic control line.
  • Assessed cMyBP-C protein expression, MYBPC3 transcription, contractile function, and calcium handling.
  • Compared cellular phenotypes to heart tissue from an HCM patient with the same mutation.

Main Results:

  • Confirmed cMyBP-C haploinsufficiency and myofibrillar disarray in mutant hiPSC-CMs, mirroring patient myocardium.
  • Observed cell-to-cell variability in MYBPC3 transcription and cMyBP-C expression.
  • Detected slowed twitch shortening velocity and accelerated Ca²⁺ transient kinetics in mutant hiPSC-CMs, with transcriptomic analysis revealing dysregulated pathways.

Conclusions:

  • A validated hiPSC-based model for MYBPC3-associated HCM was established, reflecting patient-specific protein variability and functional phenotypes.
  • Findings underscore the significance of single-cell transcriptional variability in HCM pathogenesis.
  • The model serves as a valuable tool for future hypertrophic cardiomyopathy research.
Abstract

Keywords:
MYBPC3 mutationBurst-like transcriptionDisease modelingHypertrophic cardiomyopathycMyBP-C expressionhiPSC-derived cardiomyocytes

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