Functional characterization of human myosin‐binding protein C3 variants associated with hypertrophic cardiomyopathy reveals exon‐specific cardiac phenotypes in zebrafish model

2020 ◽  
Vol 235 (11) ◽  
pp. 7870-7888 ◽  
Author(s):  
Sahar I. Da'as ◽  
Huseyin C. Yalcin ◽  
Gheyath K. Nasrallah ◽  
Iman A. Mohamed ◽  
Michail Nomikos ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Binding Protein ◽  
Functional Characterization ◽  
Zebrafish Model ◽  
Myosin Binding Protein ◽  
Myosin Binding

scholarly journals Hypertrophic cardiomyopathy-linked variants of cardiac myosin-binding protein C3 display altered molecular properties and actin interaction

2018 ◽  
Vol 475 (24) ◽  
pp. 3933-3948 ◽  
Author(s):  
Sahar I. Da'as ◽  
Khalid Fakhro ◽  
Angelos Thanassoulas ◽  
Navaneethakrishnan Krishnamoorthy ◽  
Alaaeldin Saleh ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Binding Protein ◽  
Clinical Severity ◽  
Actin Binding ◽  
Cardiac Myosin ◽  
C2 Domains ◽  
Cardiac Phenotype ◽  
Myosin Binding Protein ◽  
Myosin Binding ◽  
The Impact

The most common inherited cardiac disorder, hypertrophic cardiomyopathy (HCM), is characterized by thickening of heart muscle, for which genetic mutations in cardiac myosin-binding protein C3 (c-MYBPC3) gene, is the leading cause. Notably, patients with HCM display a heterogeneous clinical presentation, onset and prognosis. Thus, delineating the molecular mechanisms that explain how disparate c-MYBPC3 variants lead to HCM is essential for correlating the impact of specific genotypes on clinical severity. Herein, five c-MYBPC3 missense variants clinically associated with HCM were investigated; namely V1 (R177H), V2 (A216T), V3 (E258K), V4 (E441K) and double mutation V5 (V3 + V4), all located within the C1 and C2 domains of MyBP-C, a region known to interact with sarcomeric protein, actin. Injection of the variant complementary RNAs in zebrafish embryos was observed to recapitulate phenotypic aspects of HCM in patients. Interestingly, V3- and V5-cRNA injection produced the most severe zebrafish cardiac phenotype, exhibiting increased diastolic/systolic myocardial thickness and significantly reduced heart rate compared with control zebrafish. Molecular analysis of recombinant C0–C2 protein fragments revealed that c-MYBPC3 variants alter the C0–C2 domain secondary structure, thermodynamic stability and importantly, result in a reduced binding affinity to cardiac actin. V5 (double mutant), displayed the greatest protein instability with concomitant loss of actin-binding function. Our study provides specific mechanistic insight into how c-MYBPC3 pathogenic variants alter both functional and structural characteristics of C0–C2 domains leading to impaired actin interaction and reduced contractility, which may provide a basis for elucidating the disease mechanism in HCM patients with c-MYBPC3 mutations.

scholarly journals Clinical Expression in Patients With Hypertrophic Cardiomyopathy Caused by Cardiac Myosin-Binding Protein C Gene Mutation

Circulation ◽  
1999 ◽  
Vol 100 (4) ◽  
pp. 446-449 ◽  
Author(s):  
Yoshinori L. Doi ◽  
Hiroaki Kitaoka ◽  
Nobuhiko Hitomi ◽  
Manatsu Satoh ◽  
Akinori Kimura
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Gene Mutation ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Clinical Expression ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding
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