Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3 c.2373InsG in the Netherlands

Sarah Hilderink, Maike Schuldt, Max Goebel, Valentijn J Jansen, Emmy Manders, Stan Moorman, Larissa M Dorsch, Frank G van Steenbeek, Jolanda van der Velden, Diederik W D Kuster*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the cardiac myosin binding protein-C (cMyBP-C) encoding gene MYBPC3. In the Netherlands, approximately 25% of patients carry the MYBPC3 c.2373InsG founder mutation. Most patients are heterozygous (MYBPC3 +/InsG) and have highly variable phenotypic expression, whereas homozygous (MYBPC3 InsG/InsG) patients have severe HCM at a young age. To improve understanding of disease progression and genotype-phenotype relationship based on the hallmarks of human HCM, we characterized mice with CRISPR/Cas9-induced heterozygous and homozygous mutations. At 18-28 weeks of age, we assessed the cardiac phenotype of Mybpc3 +/InsG and Mybpc3 InsG/InsG mice with echocardiography, and performed histological analyses. Cytoskeletal proteins and cardiomyocyte contractility of 3-4 week old and 18-28 week old Mybpc3 c.2373InsG mice were compared to wild-type (WT) mice. Expectedly, knock-in of Mybpc3 c.2373InsG resulted in the absence of cMyBP-C and our 18-28 week old homozygous Mybpc3 c.2373InsG model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction, whereas HCM was not evident in Mybpc3 +/InsG mice. Mybpc3 InsG/InsG cardiomyocytes also presented with slowed contraction-relaxation kinetics, to a greater extent in 18-28 week old mice, partially due to increased levels of detyrosinated tubulin and desmin, and reduced cardiac troponin I (cTnI) phosphorylation. Impaired cardiomyocyte contraction-relaxation kinetics were successfully normalized in 18-28 week old Mybpc3 InsG/InsG cardiomyocytes by combining detyrosination inhibitor parthenolide and β-adrenergic receptor agonist isoproterenol. Both the 3-4 week old and 18-28 week old Mybpc3 InsG/InsG models recapitulate HCM, with a severe phenotype present in the 18-28 week old model.

Original languageEnglish
Pages (from-to)65-76
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume185
Early online date14 Oct 2023
DOIs
Publication statusPublished - Dec 2023

Keywords

  • Hypertrophic cardiomyopathy
  • Cardiac myosin binding protein c
  • Microtubule remodeling
  • Diastolic dysfunction
  • Mouse model

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