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https://hdl.handle.net/123456789/449| Τύπος: | Άρθρο σε περιοδικό |
| Τίτλος: | Hypertrophic cardiomyopathy-linked variants of cardiac myosin-binding protein C3 display altered molecular properties and actin interaction |
| Συγγραφέας: | [LA] Da’as, Sahar [EN] Fakhro, Khalid [EL] Θανάσουλας, Άγγελος[EN] Thanassoulas, Angelos [EN] Krishnamoorthy, Navaneethakrishnan [EN] Saleh, Alaaeldin [EN] Calver, Brian [EN] Safieh-Garabedian, Bared [EN] Toft, Egon [EL] Νούνεσης, Γιώργος[EN] Nounesis, George [EN] Lai, Anthony [EL] Νομικός, Μιχαήλ[EN] Nomikos, Michail |
| Ημερομηνία: | 14/12/2018 |
| Περίληψη: | 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. |
| Γλώσσα: | Αγγλικά |
| Σελίδες: | 16 |
| DOI: | 10.1042/BCJ20180685 |
| ISSN: | 0264-6021 |
| Θεματική κατηγορία: | [EL] Ιατρική βιοχημεία[EN] Medical Biochemistry [EL] Βιοφυσική[EN] Biophysics [EL] Βιολογία[EN] Biological sciences |
| Λέξεις-κλειδιά: | actin; cardiac myosin-binding protein C3; c-MYBPC3 mutations; hypertrophic cardiomyopathy; zebrafish |
| Κάτοχος πνευματικών δικαιωμάτων: | © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society |
| Ηλεκτρονική διεύθυνση του τεκμηρίου στον εκδότη: | https://portlandpress.com/biochemj/article-abstract/475/24/3933/49860/Hypertrophic-cardiomyopathy-linked-variants-of |
| Ηλεκτρονική διεύθυνση περιοδικού: | https://portlandpress.com/biochemj |
| Τίτλος πηγής δημοσίευσης: | Biochemical Journal |
| Τεύχος: | 24 |
| Τόμος: | 475 |
| Σελίδες τεκμηρίου (στην πηγή): | 3933–3948 |
| Εμφανίζεται στις συλλογές: | Μεταδιδακτορικοί ερευνητές |
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