Jessica Saganowich

Introduction: Familial hypertrophic cardiomyopathy (FHCM) is defined by having a left ventricular wall thickness greater than 15mm not due to secondary causes.¹ FHCM is cuased by inherited mutations in sarcomere genes.² The most commonly inherited mutations are in Myosin Binding Protein C (MYBPC).² Patients with FHCM experince symptoms of hypercontractility and diastolic dysfunction.¹ Currently, there are no therapeutics that target the genetic cause of patient’s symptoms. In order to develop targeted medications, researchers must understand how MYBPC mutations affect sarcomere function. Previous studies demonstrate that MYBPC is a regulatroy protein that binds to both myosin and thin filaments.^4,5,6 Specifically, MYBPC binds to myosin heads, inducing an “off position” called the Super Relaxed State (SRX). When MYBPC releases myosin, myosin transitions to an “on position” called the Disordered Relaxed State (DRX). The DRX is termed “on” because the myosin head is now able to bind to actin. Building upon our current understanding of MYBPC, this discussion reports how three recent studies increased present knowledge of MYBPC’s regulation of myosin, MYBPC mutations, and how these novel discoveries enabled the production of targeted therapeutics for patients with FHCM. Methods: The first study induced specific phosphomimetic base pair substitutions in MYBPC to observe how phosphorylation affected MYBPC’s regulation of myosin confirmation.⁵ The second study utilized MYBPC mutants and a small myosin heavy chain peptide, S2, to determine how MYBPC mutations affected contractility.⁵  The third study examined the effect of MYBPC mutations on diastolic dysfunction by measuring the duration of relaxation of three MYBPC mutants.⁷ Results: The first study showed that phosphorylation of MYBPC is the primary mechanim shifting myosin heads between the SRX and the DRX. The second study demonstrated that mutated MYBPC increased the number of myosin heads available to bind to actin, resulting in increased force of contraction.⁵ The third study supported that MYBPC mutations incrased relaxation times or diastolic dysfunction.⁷ Conclusion: Based on these findings, researchers developed two possible therapeutics for patients with FHCM, Mavacamten and MYK-461. Mavacamten is an allosteric modulator of β-cardiac myosin that stabilizes myosin heads in the SRX in the absence of MYBPC.⁸ MYK-461 is an allosteric ATPase inhibitor that prevents unbound myosin heads from binding to actin.⁷ These two examples highlight how increased understanding of MYBPC’s function and regulation of myosin head confirmation (SRX:DRX) lead to potential therapeutics for patients with FHCM.

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