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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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The Junctophilin-2 Mutation p.(Thr161Lys) Is Associated with Hypertrophic Cardiomyopathy Using Patient-Specific iPS

Joona Valtonen1, Chandra Prajapati1, Reeja Maria Cherian1

  • 1Heart Group, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.

Biomedicines
|June 28, 2023
PubMed

Insights

Modeling hypertrophic cardiomyopathy (HCM) using patient-derived induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) successfully replicated cardiac abnormalities. This approach offers a platform for studying junctophilin-2 (JPH2) mutation-related heart disease.

Area of Science:

  • Cardiovascular Genetics
  • Stem Cell Biology
  • Molecular Cardiology

Background:

  • Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease, primarily linked to sarcomeric gene mutations.
  • Non-sarcomeric protein mutations, including a Finnish founder mutation in junctophilin-2 (JPH2), also cause HCM.
  • Understanding JPH2-related HCM requires effective disease modeling.

Purpose of the Study:

  • To model the rare Finnish founder mutation in JPH2 within cardiomyocytes (CMs) derived from induced pluripotent stem cells (iPSCs).
  • To investigate the cardiac abnormalities associated with JPH2 mutations in patient-specific iPSC-CMs.
  • To establish a disease-specific cellular platform for studying JPH2-HCM.

Main Methods:

  • Reprogramming skin fibroblasts from a Finnish JPH2 p.(Thr161Lys) patient into iPSCs.
  • Differentiating patient-derived iPSCs and isogenic control lines into cardiomyocytes (iPSC-CMs) using CRISPR/Cas9.
  • Evaluating iPSC-CMs for morphological and functional characteristics of HCM.

Main Results:

  • JPH2-mutated iPSC-CMs exhibited key HCM hallmarks: cellular hypertrophy, multi-nucleation, and sarcomeric disarray.
  • These cells showed increased arrhythmia and prolonged action potential duration due to slower calcium channel inactivation.
  • Functional assessments revealed distinct beating characteristics compared to isogenic controls, supporting clinical observations.

Conclusions:

  • iPSC-derived CMs effectively model JPH2-related HCM, recapitulating patient-specific cardiac abnormalities.
  • This disease-specific iPSC-CM platform provides a valuable tool for studying the mechanisms of JPH2-HCM.
  • The model serves as a translationally relevant system for investigating genetic cardiac diseases.

Keywords:
disease modellinghypertrophic cardiomyopathyisogenic human pluripotent stem cell-derived cardiomyocytesjunctophilin-2

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