Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy

Suay-Corredera, Carmen; Pricolo, María Rosaria; Herrero-Galán, Elías; Velázquez-Carreras, Diana; Sánchez-Ortiz, David; García-Giustiniani, Diego; Delgado, Javier; Galano‐Frutos, Juan José; García-Cebollada, Helena; Vilches, Silvia; Domínguez, Fernándo; Sabater-Molina, María; Barriales‐Villa, Roberto; Frisso, Giulia; Sancho, Javier; Serrano, Luís; García‐Pavía, Pablo; Monserrat, Lorenzo; Alegre-Cebollada, Jorge

doi:10.1016/j.jbc.2021.100854

Cited by 29 publications

(40 citation statements)

References 88 publications

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“…Furthermore, a recent report has described the specific induction of two major haploinsufficiency drivers, i.e., RNA splicing alterations and protein destabilization (Fig. 8C,D), by HCM‐linked nontruncating MYBPC3 variants [263]. In this scenario, the examination of RNA splicing alterations and protein destabilization as disease‐associated molecular traits provided supporting evidence of pathogenicity for 11% of nontruncating MYBPC3 VUS in the ClinVar database [263].…”

Section: Hcm‐causing Mybpc3 Variantsmentioning

confidence: 71%

“…8C,D), by HCM‐linked nontruncating MYBPC3 variants [263]. In this scenario, the examination of RNA splicing alterations and protein destabilization as disease‐associated molecular traits provided supporting evidence of pathogenicity for 11% of nontruncating MYBPC3 VUS in the ClinVar database [263]. The disease mechanisms of these two haploinsufficiency drivers in the context of nontruncating MYBPC3 variants are described in the following subsections.…”

Section: Hcm‐causing Mybpc3 Variantsmentioning

confidence: 99%

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The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

Suay-Corredera

Alegre-Cebollada

2022

FEBS Letters

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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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Section: Hcm‐causing Mybpc3 Variantsmentioning

confidence: 71%

Section: Hcm‐causing Mybpc3 Variantsmentioning

confidence: 99%

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

Suay-Corredera

Alegre-Cebollada

2022

FEBS Letters

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“…More recently, nanomechanical alterations in mutant cardiac MyBP-C that cause hypertrophic cardiomyopathy have been detected. These alterations occur in the absence of other pathogenic molecular phenotypes (Suay-Corredera et al 2021a;Suay-Corredera et al 2021b). A decrease in mechanical stability at low forces was detected for mutant R495W, which could reduce the braking force exerted by mutant MyBP-C on actomyosin gliding.…”

Section: Muscle Proteinsmentioning

confidence: 93%

Protein nanomechanics in biological context

Alegre-Cebollada

2021

Biophys Rev

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How proteins respond to pulling forces, or protein nanomechanics, is a key contributor to the form and function of biological systems. Indeed, the conventional view that proteins are able to diffuse in solution does not apply to the many polypeptides that are anchored to rigid supramolecular structures. These tethered proteins typically have important mechanical roles that enable cells to generate, sense, and transduce mechanical forces. To fully comprehend the interplay between mechanical forces and biology, we must understand how protein nanomechanics emerge in living matter. This endeavor is definitely challenging and only recently has it started to appear tractable. Here, I introduce the main in vitro single-molecule biophysics methods that have been instrumental to investigate protein nanomechanics over the last 2 decades. Then, I present the contemporary view on how mechanical force shapes the free energy of tethered proteins, as well as the effect of biological factors such as post-translational modifications and mutations. To illustrate the contribution of protein nanomechanics to biological function, I review current knowledge on the mechanobiology of selected muscle and cell adhesion proteins including titin, talin, and bacterial pilins. Finally, I discuss emerging methods to modulate protein nanomechanics in living matter, for instance by inducing specific mechanical loss-of-function (mLOF). By interrogating biological systems in a causative manner, these new tools can contribute to further place protein nanomechanics in a biological context.

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“…Although HCM-linked missense (non-truncating) mutations in MYBPC3 are associated with more benign outcomes, functional and structural investigations of a subset of missense mutations reported disturbed cMyBPC architecture and protein–protein interactions [ 53 ] suggesting a protein poison peptide as a potential pathomechanism. However, recent have studies reported RNA splicing defects, resulting from premature stop codon, and protein destabilization cause protein haploinsufficiency in MYBPC3 missense mutations [ 54 , 55 ].…”

Section: Cardiomyopathy Causative Mutations In Sarcomeric Proteinsmentioning

confidence: 99%

“…Another mechanism through which haploinsufficiency contributes to contractile disfunction is the perturbed dynamic myosin conformations. Recent studies using mice models demonstrated that cMyBPC deficiency enhances the myosin state that enables ATP hydrolysis and thin filament interactions (DRX) and reduces the super relaxed conformation associated with low energy consumption (SRX) [ 54 ].…”

Section: Cardiomyopathy Causative Mutations In Sarcomeric Proteinsmentioning

confidence: 99%

Cardiomyocyte Dysfunction in Inherited Cardiomyopathies

Hassoun

Budde

Mügge

et al. 2021

IJMS

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Inherited cardiomyopathies form a heterogenous group of disorders that affect the structure and function of the heart. Defects in the genes encoding sarcomeric proteins are associated with various perturbations that induce contractile dysfunction and promote disease development. In this review we aimed to outline the functional consequences of the major inherited cardiomyopathies in terms of myocardial contraction and kinetics, and to highlight the structural and functional alterations in some sarcomeric variants that have been demonstrated to be involved in the pathogenesis of the inherited cardiomyopathies. A particular focus was made on mutation-induced alterations in cardiomyocyte mechanics. Since no disease-specific treatments for familial cardiomyopathies exist, several novel agents have been developed to modulate sarcomere contractility. Understanding the molecular basis of the disease opens new avenues for the development of new therapies. Furthermore, the earlier the awareness of the genetic defect, the better the clinical prognostication would be for patients and the better the prevention of development of the disease.

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Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy

Cited by 29 publications

References 88 publications

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

The mechanics of the heart: zooming in on hypertrophic cardiomyopathy and cMyBP‐C

Protein nanomechanics in biological context

Cardiomyocyte Dysfunction in Inherited Cardiomyopathies

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