MYBPC3 in hypertrophic cardiomyopathy: from mutation identification to RNA-based correction

Behrens-Gawlik, Verena; Mearini, Giulia; Gedicke‐Hornung, Christina; Richard, P.; Carrier, Lucie

doi:10.1007/s00424-013-1409-7

Cited by 37 publications

(41 citation statements)

References 64 publications

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“…Classical treatments of HCM target symptoms and LV outflow tract obstruction with pharmacological and/or surgical treatments, but do not address the cause of the disease 29,30 . New strategies targeting the endogenous mutant pre-mRNA or RNA such as exon skipping, exon inclusion, trans-splicing and ARTICLE RNA silencing, opened the perspective for a causal therapy for patients with HCM 2,21,22,31,32 . These proof-of-concept studies still have major limitations.…”

Section: Discussionmentioning

confidence: 99%

“…Out of them, MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) is the most frequently mutated gene. More than 64% of MYBPC3 mutations are truncating, leading to unstable mutant polypeptides [2][3][4][5] . Findings in humans as well as in cat and mouse HCM models indicate that the most prevalent disease mechanism is haploinsufficiency, even for MYBPC3 missense mutations [6][7][8] .…”

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confidence: 99%

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Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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“…Mutations in MYBPC3, a thick filament gene encoding cMyBP-C, is genetically linked to 40-50% distinct HCM-causing mutations, making MYH7 and MYBPC3 the most common genes underlying FHC-based disease [3,10]. Despite the predominance of these gene mutations in HCM, MYH7 mutations typically result in amino acid substitutions whereas MYBPC3 variants disrupt the reading frame, leading to a truncated cMyBP-C protein and, often, haploinsufficiency [3].…”

Section: Genotype To Phenotypementioning

confidence: 99%

“…Despite the predominance of these gene mutations in HCM, MYH7 mutations typically result in amino acid substitutions whereas MYBPC3 variants disrupt the reading frame, leading to a truncated cMyBP-C protein and, often, haploinsufficiency [3]. Considering the role of β-MyHC in cardiomyocyte force generation, a missense mutation within a known critical domain of the MYH7 gene can be more directly linked to a contractile deficit, usually through a gain-of-function and increased energy cost [11][12][13].…”

Section: Genotype To Phenotypementioning

confidence: 99%

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Inherited Cardiomyopathies: From Genotype to Phenotype

Lopez-Pier¹,

Lipovka²,

Constantopoulos³

et al. 2017

Cardiomyopathies - Types and Treatments

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The heart undergoes extensive morphological, metabolic, and energetic remodeling in response to inherited, or familial, hypertrophic cardiomyopathies (FHC). Myocyte contractile perturbations downstream of Ca 2+ , the so-called sarcomere-controlled mechanisms, may represent the earliest indicators of this remodeling. We can now state that the dynamics of cardiac contraction and relaxation during the progression of FHC are governed by downstream mechanisms, particularly the kinetics and energetics of actin and myosin interaction to drive the trajectory of pathological cardiac remodeling. This notion is unambiguously supported by elegant studies above linking inheritable FHCcausing mutations to cardiomyopathies, known to disturb contractile function and alter the energy landscape of the heart. Although studies examining the biophysical properties of cardiac myocytes with FHC-causing mutations have yielded a cellular and molecular understanding of myofilament function, this knowledge has had limited translational success. This is driven by a critical failure in elucidating an integrated and sequential link among the changing energy landscape, myofilament function, and initiated signaling pathways in response to FHC. Similarly, there continues to be a major gap in understanding the cellular and molecular mechanisms contributing to sex differences in FHC development and progression. The primary reason for this gap is a lack of a "unifying" or "central" hypothesis that integrates signaling cascades, energetics, sex and FHC.

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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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MYBPC3 in hypertrophic cardiomyopathy: from mutation identification to RNA-based correction

Cited by 37 publications

References 64 publications

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

Inherited Cardiomyopathies: From Genotype to Phenotype

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

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