The W792R HCM missense mutation in the C6 domain of cardiac myosin binding protein-C increases contractility in neonatal mouse myocardium.

Autor: Mertens J; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America; UW Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America., De Lange WJ; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America; UW Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America., Farrell ET; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America; UW Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America., Harbaugh EC; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America; UW Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America., Gauchan A; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America; UW Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America., Fitzsimons DP; UW Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America., Moss RL; UW Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America., Ralphe JC; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America; UW Cardiovascular Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, United States of America. Electronic address: jcralphe@pediatrics.wisc.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Oct; Vol. 195, pp. 14-23. Date of Electronic Publication: 2024 Jul 25.
DOI: 10.1016/j.yjmcc.2024.07.007
Abstrakt: Missense mutations in cardiac myosin binding protein C (cMyBP-C) are known to cause hypertrophic cardiomyopathy (HCM). The W792R mutation in the C6 domain of cMyBP-C causes severe, early onset HCM in humans, yet its impact on the function of cMyBP-C and the mechanism through which it causes disease remain unknown. To fully characterize the effect of the W792R mutation on cardiac morphology and function in vivo, we generated a murine knock-in model. We crossed heterozygous W792R WR mice to produce homozygous mutant W792R RR , heterozygous W792R WR , and control W792R WW mice. W792R RR mice present with cardiac hypertrophy, myofibrillar disarray and fibrosis by postnatal day 10 (PND10), and do not survive past PND21. Full-length cMyBP-C is present at similar levels in W792R WW , W792R WR and W792R RR mice and is properly incorporated into the sarcomere. Heterozygous W792R WR mice displayed normal heart morphology and contractility. Permeabilized myocardium from PND10 W792R RR mice showed increased Ca 2+ sensitivity, accelerated cross-bridge cycling kinetics, decreased cooperativity in the activation of force, and increased expression of hypertrophy-related genes. In silico modeling suggests that the W792R mutation destabilizes the fold of the C6 domain and increases torsion in the C5-C7 region, possibly impacting regulatory interactions of cMyBP-C with myosin and actin. Based on the data presented here, we propose a model in which mutant W792R cMyBP-C preferentially forms Ca 2+ sensitizing interactions with actin, rather than inhibitory interactions with myosin. The W792R-cMyBP-C mouse model provides mechanistic insights into the pathology of this mutation and may provide a mechanism by which other central domain missense mutations in cMyBP-C may alter contractility, leading to HCM.
(Copyright © 2024. Published by Elsevier Ltd.)
Databáze: MEDLINE
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