Generation of induced pluripotent stem cells from an individual with early onset and severe hypertrophic...

Area of Science:

• Cardiovascular Genetics
• Stem Cell Biology
• Molecular Cardiology

Background:

• Hypertrophic cardiomyopathy (HCM) is often caused by MYBPC3 gene mutations, primarily nonsense or frameshift variants leading to reduced cardiac myosin-binding protein C (cMyBP-C) levels.
• The pathogenicity of missense MYBPC3 variants and their contribution to HCM remain incompletely understood.
• Induced pluripotent stem cells (iPSCs) from HCM patients offer a powerful in vitro model for disease investigation.

Purpose of the Study:

• To generate and characterize novel iPSC lines from an HCM patient with the MYBPC3: c.772G>A variant.
• To establish a cellular model for studying the molecular mechanisms of HCM caused by this specific MYBPC3 variant.
• To provide a resource for investigating factors contributing to severe HCM phenotypes.

Main Methods:

• Generation of iPSC lines from peripheral blood mononuclear cells (PBMCs) of an HCM patient.
• Karyotyping to assess chromosomal stability.
• Assessment of pluripotency markers and trilineage differentiation capacity.
• Characterization of the MYBPC3: c.772G>A variant, noting its impact on splicing and potential frameshift.

Main Results:

• Two novel iPSC lines were successfully generated from an HCM patient with the MYBPC3: c.772G>A variant.
• The generated iPSC lines possess a normal karyotype and maintain pluripotency.
• These iPSCs demonstrate the ability to differentiate into cardiomyocytes, confirming their utility for disease modeling.

Conclusions:

• The novel iPSC lines represent a valuable addition to the available resources for studying MYBPC3-related HCM.
• These iPSCs offer a platform to investigate the functional consequences of the MYBPC3: c.772G>A variant, including its splicing-defective nature.
• The iPSC model can facilitate research into the genetic underpinnings of severe HCM phenotypes and potential secondary genetic modifiers.