A Hypertrophic Cardiomyopathy-associated MYBPC3 Mutation Common in Populations of South Asian Descent Causes Contractile Dysfunction

Kuster, Diederik W.D.; Govindan, Serengulam V.; Springer, Tzvia I.; Martin, J.L.; Finley, Natosha L.; Sadayappan, Sakthivel

doi:10.1074/jbc.m114.607911

Cited by 22 publications

(20 citation statements)

References 52 publications

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“…Given that HCM is as an inherited cardiomyopathy,17 its clinical features and prognosis are likely to be variable depending on ethnicity 18–20. Hence, it is essential to validate the HCM Risk-SCD calculator in a separate, independent and sizeable cohort of the Asian patients with HCM.…”

Section: Discussionmentioning

confidence: 99%

Validation of the hypertrophic cardiomyopathy risk-sudden cardiac death calculator in Asians

Choi

Kim

Lee

et al. 2019

Heart

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ObjectiveThe hypertrophic cardiomyopathy (HCM) risk-sudden cardiac death (SCD) calculator endorsed by the 2014 European Society of Cardiology has not been independently validated in the Asians. We aimed to investigate whether the HCM Risk-SCD calculator effectively predicts SCD in Korean HCM population.MethodsAn observational, longitudinal cohort study was performed in 730 patients with HCM from 2007 to 2017. The primary endpoint was a composite of SCD and appropriate implantable cardioverter-defibrillator (ICD) therapy.ResultsDuring a follow-up period of 4288 person-years, 16 (2.2%) patients reached the primary endpoint. This validation study revealed a calibration slope of 0.892 and C-statistics of 0.718. The primary endpoint occurred in 1.1% (7/615), 4.6% (3/65) and 12.0% (6/50) of low-risk, intermediate-risk and high-risk groups, respectively. Although most patients (85.2%) without the primary endpoint were classified into the low-risk group, 7 of 11 SCD (63.6%) occurred in the low-risk group. In univariable and multivariable analysis, sex (woman) was significantly associated with the primary endpoint and emerged as independent predictor. The addition of sex to the HCM Risk-SCD calculator significantly improved the predictive value of the primary endpoint (net reclassification improvement 0.557, p=0.015).ConclusionsIn the Korean HCM population, the HCM Risk-SCD calculator had a high negative predictive value and accuracy for predicting SCD or appropriate ICD therapy, but misclassified a few patients experiencing the primary endpoint as low-risk or intermediate-risk groups.

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Section: Discussionmentioning

confidence: 99%

Validation of the hypertrophic cardiomyopathy risk-sudden cardiac death calculator in Asians

Choi

Kim

Lee

et al. 2019

Heart

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“…These two domains can bind to Titin protein and stabilise the structure of the sarcomere. 18 The deletion mutation, c.3041delT/p.L1014RfsX6, may disturb the structure of the sarcomere by affecting these two domains of Myosin Binding Protein C and lead to dilated cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing reveals doubly novel heterozygous Myosin Binding Protein C and Titin mutations in a Chinese patient with severe dilated cardiomyopathy

et al. 2018

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Whole-exome sequencing combined with cardiomyopathy-related genes list were used to analyse the mutations of the proband. Co-segregation analysis was performed by Sanger sequencing.Results and conclusionsTwo novel heterozygous mutations - Myosin Binding Protein C: p.L1014RfsX6 and Titin: p.R9793X - were identified in the proband. The deletion mutation c.3041delT/p.L1014RfsX6 caused a premature stop codon at position 1020 in exon 28 of the Myosin Binding Protein C. The nonsense mutation, c.29377 C>T/ p. R9793X, of Titin was located in the highly evolutionarily conserved domain, resulting in truncation of the Titin protein as well. Co-segregation analysis further revealed that the Myosin Binding Protein C mutation came from his mother and the Titin mutation came from his father. Both mutations are reported in dilated cardiomyopathy patients for the first time. Our study not only provides a unique example of the genes and molecular mechanisms involved in dilated cardiomyopathy but also expands the spectrum of Myosin Binding Protein C and Titin mutations and contributes to the genetic diagnosis and counselling of dilated cardiomyopathy patients.

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“…The backbone chemical shift assignments for stable isotope-labeled ssC1C2 were determined in part by direct comparison to the previously known values (BMRB accession numbers 17,867, 11,212 and 5591). The following suite of triple-resonance experiments were used to confirm assignments: 15 N edited NOESY-HSQC, CβCαCONH, HNCA, TROSY-HNCO, and TROSY-HNCA [28]. Samples of [ 15 N, 13 C, 2 H]Ca 2+ -CaM were also suspended at 130 µM in NMR buffer in the presence of 10 mM CaCl 2 .…”

Section: Nuclear Magnetic Resonance Spectroscopy (Nmr)mentioning

confidence: 99%

“…It is reported to span between thin and thick filaments [1] while participating in the regulation of actin-myosin association. The N-terminal domains of MyBP-C interact with actin [2][3][4][5][6][7][8], myosin S2 [9,10], and the regulatory light chains [11], while the C-terminal domains are tethered to titin [12] and the myosin rod [13][14][15]. There are three different isoforms of MyBP-C expressed in striated muscles: cardiac (cMyBP-C), fast skeletal (fsMyBP-C), and slow skeletal (ssMyBP-C).…”

Section: Introductionmentioning

confidence: 99%

Calcium-Dependent Interaction Occurs between Slow Skeletal Myosin Binding Protein C and Calmodulin

et al. 2017

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Abstract:Myosin binding protein C (MyBP-C) is a multi-domain protein that participates in the regulation of muscle contraction through dynamic interactions with actin and myosin. Three primary isoforms of MyBP-C exist: cardiac (cMyBP-C), fast skeletal (fsMyBP-C), and slow skeletal (ssMyBP-C). The N-terminal region of cMyBP-C contains the M-motif, a three-helix bundle that binds Ca 2+ -loaded calmodulin (CaM), but less is known about N-terminal ssMyBP-C and fsMyBP-C. Here, we characterized the conformation of a recombinant N-terminal fragment of ssMyBP-C (ssC1C2) using differential scanning fluorimetry, nuclear magnetic resonance, and molecular modeling. Our studies revealed that ssC1C2 has altered thermal stability in the presence and absence of CaM. We observed that site-specific interaction between CaM and the M-motif of ssC1C2 occurs in a Ca 2+ -dependent manner. Molecular modeling supported that the M-motif of ssC1C2 likely adopts a three-helix bundle fold comparable to cMyBP-C. Our study provides evidence that ssMyBP-C has overlapping structural determinants, in common with the cardiac isoform, which are important in controlling protein-protein interactions. We shed light on the differential molecular regulation of contractility that exists between skeletal and cardiac muscle.

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A Hypertrophic Cardiomyopathy-associated MYBPC3 Mutation Common in Populations of South Asian Descent Causes Contractile Dysfunction

Cited by 22 publications

References 52 publications

Validation of the hypertrophic cardiomyopathy risk-sudden cardiac death calculator in Asians

Validation of the hypertrophic cardiomyopathy risk-sudden cardiac death calculator in Asians

Whole-exome sequencing reveals doubly novel heterozygous Myosin Binding Protein C and Titin mutations in a Chinese patient with severe dilated cardiomyopathy

Calcium-Dependent Interaction Occurs between Slow Skeletal Myosin Binding Protein C and Calmodulin

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