TY - JOUR
T1 - Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3c.2373InsG in the Netherlands
AU - Hilderink, Sarah
AU - Schuldt, Maike
AU - Goebel, Max
AU - Jansen, Valentijn J.
AU - Manders, Emmy
AU - Moorman, Stan
AU - Dorsch, Larissa M.
AU - van Steenbeek, Frank G.
AU - van der Velden, Jolanda
AU - Kuster, Diederik W. D.
N1 - Funding Information: This work was supported by the Netherlands Cardiovascular Research (CVON) and Dutch CardioVascular Alliance (DCVA) initiatives of the Dutch Heart Foundation ( 2020B005 DCVA-DOUBLE-DOSE ), and NWO-ZonMW ( 91818602 VICI grant). Publisher Copyright: © 2023 The Authors
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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 MYBPC3c.2373InsG founder mutation. Most patients are heterozygous (MYBPC3+/InsG) and have highly variable phenotypic expression, whereas homozygous (MYBPC3InsG/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 Mybpc3InsG/InsG mice with echocardiography, and performed histological analyses. Cytoskeletal proteins and cardiomyocyte contractility of 3–4 week old and 18–28 week old Mybpc3c.2373InsG mice were compared to wild-type (WT) mice. Expectedly, knock-in of Mybpc3c.2373InsG resulted in the absence of cMyBP-C and our 18–28 week old homozygous Mybpc3c.2373InsG model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction, whereas HCM was not evident in Mybpc3+/InsG mice. Mybpc3InsG/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 Mybpc3InsG/InsG cardiomyocytes by combining detyrosination inhibitor parthenolide and β-adrenergic receptor agonist isoproterenol. Both the 3–4 week old and 18–28 week old Mybpc3InsG/InsG models recapitulate HCM, with a severe phenotype present in the 18–28 week old model.
AB - 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 MYBPC3c.2373InsG founder mutation. Most patients are heterozygous (MYBPC3+/InsG) and have highly variable phenotypic expression, whereas homozygous (MYBPC3InsG/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 Mybpc3InsG/InsG mice with echocardiography, and performed histological analyses. Cytoskeletal proteins and cardiomyocyte contractility of 3–4 week old and 18–28 week old Mybpc3c.2373InsG mice were compared to wild-type (WT) mice. Expectedly, knock-in of Mybpc3c.2373InsG resulted in the absence of cMyBP-C and our 18–28 week old homozygous Mybpc3c.2373InsG model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction, whereas HCM was not evident in Mybpc3+/InsG mice. Mybpc3InsG/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 Mybpc3InsG/InsG cardiomyocytes by combining detyrosination inhibitor parthenolide and β-adrenergic receptor agonist isoproterenol. Both the 3–4 week old and 18–28 week old Mybpc3InsG/InsG models recapitulate HCM, with a severe phenotype present in the 18–28 week old model.
KW - Cardiac myosin binding protein c
KW - Diastolic dysfunction
KW - Hypertrophic cardiomyopathy
KW - Microtubule remodeling
KW - Mouse model
UR - http://www.scopus.com/inward/record.url?scp=85175249639&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.yjmcc.2023.10.008
DO - https://doi.org/10.1016/j.yjmcc.2023.10.008
M3 - Article
C2 - 37844837
SN - 0022-2828
VL - 185
SP - 65
EP - 76
JO - Journal of molecular and cellular cardiology
JF - Journal of molecular and cellular cardiology
ER -