| First Author | Hilderink S | Year | 2023 |
| Journal | J Mol Cell Cardiol | Volume | 185 |
| Pages | 65-76 | PubMed ID | 37844837 |
| Mgi Jnum | J:342404 | Mgi Id | MGI:7548174 |
| Doi | 10.1016/j.yjmcc.2023.10.008 | Citation | Hilderink S, et al. (2023) Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands. J Mol Cell Cardiol 185:65-76 |
| abstractText | 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 beta-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. |
