Journal
FEBS LETTERS
Volume 596, Issue 6, Pages 703-746Publisher
WILEY
DOI: 10.1002/1873-3468.14301
Keywords
cardiac myosin-binding protein C; hypertrophic cardiomyopathy; myosin; nontruncating MYBPC3 variants; protein nanomechanics; protein stability; RNA splicing; sarcomere contraction; truncating MYBPC3 variants; variants of uncertain significance
Funding
- Spanish Ministry of Science and Innovation [MCIN/AEI/10.13039/501100011033, PID2020120426GB-I00]
- Severo Ochoa Program for Centers of Excellence in RD [SEV-2015-0505, CEX2020-001041-S]
- Comunidad de Madrid [S2018/NMT-4443]
- European Social Fund (ESF)
- European Regional Development Fund (ERDF)
- Instituto de Salud Carlos III (ISCIII), MCIN
- Pro CNIC Foundation
- FPI-SO predoctoral fellowship [BES-2016-076638]
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Hypertrophic cardiomyopathy (HCM) is the most common inherited disorder of the heart, characterized by cardiac muscle hypertrophy and hypercontractility. This review summarizes the clinical and genetic aspects of HCM and provides updated information on therapeutic options targeting sarcomere mechanical activity. The authors also discuss the correlation between altered mechanical properties of cMyBP-C and HCM development.
Hypertrophic cardiomyopathy (HCM), a disease characterized by cardiac muscle hypertrophy and hypercontractility, is the most frequently inherited disorder of the heart. HCM is mainly caused by variants in genes encoding proteins of the sarcomere, the basic contractile unit of cardiomyocytes. The most frequently mutated among them is MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), a key regulator of sarcomere contraction. In this review, we summarize clinical and genetic aspects of HCM and provide updated information on the function of the healthy and HCM sarcomere, as well as on emerging therapeutic options targeting sarcomere mechanical activity. Building on what is known about cMyBP-C activity, we examine different pathogenicity drivers by which MYBPC3 variants can cause disease, focussing on protein haploinsufficiency as a common pathomechanism also in nontruncating variants. Finally, we discuss recent evidence correlating altered cMyBP-C mechanical properties with HCM development.
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