Haploinsufficiency MYBPC3 mutations: Another stress induced cardiomyopathy? Let's take a look!

Strande, Jennifer L.

doi:10.1016/j.yjmcc.2014.12.008

Cited by 5 publications

(4 citation statements)

References 36 publications

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“…An interesting unresolved question is whether MYBPC3 mutation carriers remain asymptomatic until a certain threshold of haploinsufficiency is reached. Some recent studies have raised the question of whether stress can trigger reduction in MYBPC3 levels and remodeling in asymptomatic individuals, which may explain the variable age of onset of MYBPC3-linked HCM [72]. Schlossarek et al found that adrenergic challenge via one week of treatment with isoprenaline and phenylephrine induced ventricular hypertrophy and proteasome dysfunction in previously phenotype-negative heterozygous MYBPC3 mutant mice [71].…”

Section: Haploinsufficiency In Hcmmentioning

confidence: 99%

Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy

Glazier

Thompson

Day

2018

Pflugers Arch - Eur J Physiol

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Mutations in cardiac myosin binding protein C (MYBPC3) represent the most frequent cause of familial hypertrophic cardiomyopathy (HCM), making up approximately 50% of identified HCM mutations[4]. MYBPC3 is distinct among other sarcomere genes associated with HCM in that truncating mutations make up the vast majority, whereas non-truncating mutations predominant in other sarcomere genes[4,84]. Several studies using myocardial tissue from HCM patients have found reduced abundance of wild-type MYBPC3 compared to control hearts[34,43,79,80,47,28], suggesting haploinsufficiency of full-length MYBPC3. Further, decreased mutant versus wild-type mRNA and lack of truncated mutant MYBPC3 protein has been demonstrated, highlighting the presence of allelic imbalance[34,43,79,80,47,28]. In this review, we will begin by introducing allelic imbalance and haploinsufficiency, highlighting the broad role each plays within the spectrum of human disease. We will subsequently focus on the roles allelic imbalance and haploinsufficiency play within MYBPC3-linked HCM. Finally, we will explore the implications of these findings on future directions of HCM research. An improved understanding of allelic imbalance and haploinsufficiency may help us better understand genotype-phenotype relationships in HCM and develop novel targeted therapies, providing exciting future research opportunities.

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Section: Haploinsufficiency In Hcmmentioning

confidence: 99%

Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy

Glazier

Thompson

Day

2018

Pflugers Arch - Eur J Physiol

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“…A knock-in mouse model with an exon 30 truncating MYBPC3 mutation has normal levels of total cMyBP-C expression and normal cardiac morphology [19], but Barefield et al [18] recently found that transaortic banding induced cardiac stress induces transient haploinsufficiency of cMyBP-C in this model. At this time, it remains unclear whether haploinsufficiency is responsible for either initiation or progression of HCM in humans [12,20]. …”

Section: Introductionmentioning

confidence: 99%

Deficient cMyBP-C protein expression during cardiomyocyte differentiation underlies human hypertrophic cardiomyopathy cellular phenotypes in disease specific human ES cell derived cardiomyocytes

Rocha

Guerrero-Serna

Helms

et al. 2016

Journal of Molecular and Cellular Cardiology

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Aims Mutations of cardiac sarcomere genes have been identified to cause HCM, but the molecular mechanisms that lead to cardiomyocyte hypertrophy and risk for sudden death are uncertain. The aim of this study was to examine HCM disease mechanisms at play during cardiac differentiation of human HCM specific pluripotent stem cells. Methods and results We generated a human embryonic stem cell (hESC) line carrying a naturally occurring mutation of MYPBC3 (c.2905 + 1 G > A) to study HCM pathogenesis during cardiac differentiation. HCM-specific hESC-derived cardiomyocytes (hESC-CMs) displayed hallmark aspects of HCM including sarcomere disarray, hypertrophy and impaired calcium impulse propagation. HCM hESC-CMs presented a transient haploinsufficiency of cMyBP-C during cardiomyocyte differentiation, but by day 30 post-differentiation cMyBP-C levels were similar to control hESC-CMs. Gene transfer of full-length MYBPC3 during differentiation prevented hypertrophy, sarcomere disarray and improved calcium impulse propagation in HCM hESC-CMs. Conclusion(s) These findings point to the critical role of MYBPC3 during sarcomere assembly in cardiac myocyte differentiation and suggest developmental influences of MYBPC3 truncating mutations on the mature hypertrophic phenotype.

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“…Myosin binding protein-C cardiac isoform (MYBPC3) is a thick filament accessory protein of the striated muscle sarcomere A-band, and mutations in MYBPC3 are implicated in both Hypertrophic Cardiomyopathy (HCM) and Dilated Cardiomyopathy (DCM) 1 . The molecular mechanisms by which MYBPC3 mutations lead to the contractile deficits for DCM phenotypes remain elusive, while increasing reports from mouse models indicated that stress played a role in the initiation and progression of the physiopathology process associated with MYBPC3 mutations 2 . Currently, hiPSC technology has provided previously unanticipated possibilities to model human heart diseases in cell culture, but these models have tended to simplify the diseases as monogenic, hereditary forms of diseases, which neglects the diversity in disease phenotypes resulting from genetic-environmental interactions.…”

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confidence: 99%

Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload

Huebsch

Koo

et al. 2018

Nat Biomed Eng

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The integration of in vitro cardiac tissue models, human induced pluripotent stem cells (hiPSCs) and genome-editing tools allows for the enhanced interrogation of physiological phenotypes and the recapitulation of disease pathologies. Here, in a cardiac tissue model consisting of filamentous 3D matrices populated with cardiomyocytes (CMs) derived from healthy wild-type hiPSCs (WT hiPSC-CMs) or from isogenic hiPSCs deficient in the sarcomere protein cardiac myosin binding protein C (MYBPC3 −/− hiPSC-CMs), we show that the WT microtissues adapted to the mechanical environment with increased contraction force commensurate to matrix stiffness, whereas the MYBPC3 −/− microtissues exhibited impaired force-development kinetics regardless of matrix stiffness and deficient contraction force only when grown on matrices with high fiber stiffness. Under mechanical overload, the MYBPC3 −/− microtissues had a higher degree of calcium transient abnormalities, and exhibited an accelerated decay of calcium dynamics as well as calcium desensitization, which accelerated when contracting against stiffer fibers. Our findings suggest that MYBPC3 deficiency and the presence of environmental stresses synergistically lead to contractile deficits in the cardiac tissues.

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Haploinsufficiency MYBPC3 mutations: Another stress induced cardiomyopathy? Let's take a look!

Cited by 5 publications

References 36 publications

Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy

Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy

Deficient cMyBP-C protein expression during cardiomyocyte differentiation underlies human hypertrophic cardiomyopathy cellular phenotypes in disease specific human ES cell derived cardiomyocytes

Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload

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