A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia.
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ABSTRACT:
SUBMITTER: Dhandapany PS
PROVIDER: S-EPMC2697598 | biostudies-literature | 2009 Feb
REPOSITORIES: biostudies-literature
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A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia.
Dhandapany Perundurai S PS Sadayappan Sakthivel S Xue Yali Y Powell Gareth T GT Rani Deepa Selvi DS Nallari Prathiba P Rai Taranjit Singh TS Khullar Madhu M Soares Pedro P Bahl Ajay A Tharkan Jagan Mohan JM Vaideeswar Pradeep P Rathinavel Andiappan A Narasimhan Calambur C Ayapati Dharma Rakshak DR Ayub Qasim Q Mehdi S Qasim SQ Oppenheimer Stephen S Richards Martin B MB Price Alkes L AL Patterson Nick N Reich David D Singh Lalji L Tyler-Smith Chris C Thangaraj Kumarasamy K
Nature genetics 20090118 2
Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3-13), P = 2 x 10(-6); replic ...[more]
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Project description:More than 350 individual MYPBC3 mutations have been identified in patients with inherited hypertrophic cardiomyopathy (HCM), thus representing 40–50% of all HCM mutations, making it the most frequently mutated gene in HCM. HCM is considered a disease of the sarcomere and is characterized by left ventricular hypertrophy, myocyte disarray and diastolic dysfunction. MYBPC3 encodes for the thick filament associated protein cardiac myosin-binding protein C (cMyBP-C), a signaling node in cardiac myocytes that contributes to the maintenance of sarcomeric structure and regulation of contraction and relaxation. This review aims to provide a succinct overview of how mutations in MYBPC3 are considered to affect the physiological function of cMyBP-C, thus causing the deleterious consequences observed inHCM patients. Importantly, recent advances to causally treat HCM by repairing MYBPC3 mutations by gene therapy are discussed here, providing a promising alternative to heart transplantation for patients with a fatal form of neonatal cardiomyopathy due to bi-allelic truncating MYBPC3 mutations.
| S-EPMC6660134 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) results from mutations in genes encoding sarcomeric proteins, most often MYBPC3, which encodes cardiac myosin binding protein-C (cMyBP-C). A recently discovered HCM-associated 25-base pair deletion in MYBPC3 is inherited in millions worldwide. Although this mutation causes changes in the C10 domain of cMyBP-C (cMyBP-C(C10mut)), which binds to the light meromyosin (LMM) region of the myosin heavy chain, the underlying molecular mechanism causing HCM is unknown. In this study, adenoviral expression of cMyBP-C(C10mut) in cultured adult rat cardiomyocytes was used to investigate protein localization and evaluate contractile function and Ca(2+) transients, compared with wild-type cMyBP-C expression (cMyBP-C(WT)) and controls. Forty-eight hours after infection, 44% of cMyBP-C(WT) and 36% of cMyBP-C(C10mut) protein levels were determined in total lysates, confirming equal expression. Immunofluorescence experiments showed little or no localization of cMyBP-C(C10mut) to the C-zone, whereas cMyBP-C(WT) mostly showed C-zone staining, suggesting that cMyBP-C(C10mut) could not properly integrate in the C-zone of the sarcomere. Subcellular fractionation confirmed that most cMyBP-C(C10mut) resided in the soluble fraction, with reduced presence in the myofilament fraction. Also, cMyBP-C(C10mut) displayed significantly reduced fractional shortening, sarcomere shortening, and relaxation velocities, apparently caused by defects in sarcomere function, because Ca(2+) transients were unaffected. Co-sedimentation and protein cross-linking assays confirmed that C10(mut) causes the loss of C10 domain interaction with myosin LMM. Protein homology modeling studies showed significant structural perturbation in cMyBP-C(C10mut), providing a potential structural basis for the alteration in its mode of interaction with myosin LMM. Therefore, expression of cMyBP-C(C10mut) protein is sufficient to cause contractile dysfunction in vitro.
| S-EPMC4342493 | biostudies-literature
Project description:BackgroundMutations in Myosin Binding Protein C (MYBPC3) are one of the most frequent causes of cardiomyopathies in the world, but not much data are available in India.MethodsWe carried out targeted direct sequencing of MYBPC3 in 115 hypertrophic (HCM) and 127 dilated (DCM) cardiomyopathies against 197 ethnically matched healthy controls from India.ResultsWe detected 34 single nucleotide variations in MYBPC3, of which 19 were novel. We found a splice site mutation [(IVS6+2T) T>G] and 16 missense mutations in Indian cardiomyopathies [5 in HCM; E258K, T262S, H287L, R408M, V483A: 4 in DCM; T146N, V321L, A392T, E393K and 7 in both HCM and DCM; L104M, V158M, S236G, R272C, T290A, G522E, A626V], but those were absent in 197 normal healthy controls. Interestingly, we found 7 out of 16 missense mutations (V158M, E258K, R272C, A392T, V483A, G522E, and A626V) in MYBPC3 were altering the evolutionarily conserved native amino acids, accounted for 8.7% and 6.3% in HCM and DCM, respectively. The bioinformatic tools predicted that those 7 missense mutations were pathogenic. Moreover, the co-segregation of those 7 mutations in families further confirmed their pathogenicity. Remarkably, we also identified compound mutations within the MYBPC3 gene of 6 cardiomyopathy patients (5%) with more severe disease phenotype; of which, 3 were HCM (2.6%) [(1. K244K + E258K + (IVS6+2T) T>G); (2. L104M + G522E + A626V); (3. P186P + G522E + A626V]; and 3 were DCM (2.4%) [(1. 5'UTR + A392T; 2. V158M+G522E; and 3.V158M + T262T + A626V].ConclusionThe present comprehensive study on MYBPC3 has revealed both single and compound mutations in MYBPC3 and their association with disease in Indian Population with Cardiomyopathies. Our findings may perhaps help in initiating diagnostic strategies and eventually recognizing the targets for therapeutic interventions.
| S-EPMC10518145 | biostudies-literature
Project description:The mechanisms by which truncating mutations in MYBPC3 (encoding cardiac myosin-binding protein C; cMyBPC) or myosin missense mutations cause hypercontractility and poor relaxation in hypertrophic cardiomyopathy (HCM) are incompletely understood. Using genetic and biochemical approaches, we explored how depletion of cMyBPC altered sarcomere function. We demonstrated that stepwise loss of cMyBPC resulted in reciprocal augmentation of myosin contractility. Direct attenuation of myosin function, via a damaging missense variant (F764L) that causes dilated cardiomyopathy (DCM), normalized the increased contractility from cMyBPC depletion. Depletion of cMyBPC also altered dynamic myosin conformations during relaxation, enhancing the myosin state that enables ATP hydrolysis and thin filament interactions while reducing the super relaxed conformation associated with energy conservation. MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation deficits and restored normal contractility in mouse and human cardiomyocytes with MYBPC3 mutations. These data define dosage-dependent effects of cMyBPC on myosin that occur across the cardiac cycle as the pathophysiologic mechanisms by which MYBPC3 truncations cause HCM. Therapeutic strategies to attenuate cMyBPC activity may rescue depressed cardiac contractility in patients with DCM, whereas inhibiting myosin by MYK-461 should benefit the substantial proportion of patients with HCM with MYBPC3 mutations.
| S-EPMC7184965 | biostudies-literature
Project description:Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~?40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25-base pair deletion in intron 32 of MYBPC3 (MYBPC3?25bp) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3?25bp carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3?25bp variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3?25bp pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.
| S-EPMC7429610 | biostudies-literature
Project description:The myosin-binding protein C isoform 3 (MYBPC3) variant Arg502Trp has been identified in multiple hypertrophic cardiomyopathy (HCM) cases, but compelling evidence to support or refute the pathogenicity of this variant is lacking.To determine the prevalence, origin and clinical significance of the MYBPC3 Arg502Trp variant.The prevalence of MYBPC3 Arg502Trp was ascertained in 1414 sequential HCM patients of primarily European descent. MYBPC3 Arg502Trp was identified in 34 of these 1414 unrelated HCM patients. Segregation of MYBPC3 Arg502Trp with clinical status was assessed in family members. Disease haplotypes were examined in 17 families using two loci flanking MYBPC3. Family studies identified an additional 43 variant carriers, many with manifest disease, yielding a calculated odds ratio of 11 000:1 for segregation of MYBPC3 Arg502Trp with HCM. Analyses in 17 families showed at least 4 independent haplotypes flanked MYBPC3 Arg502Trp. Eight individuals (4 probands and 4 family members) also had another sarcomere protein gene mutation. Major adverse clinical events occurred in approximately 30% of MYBPC3 Arg502Trp carriers by age 50; these were significantly more likely (P<0.0001) when another sarcomere mutation was present.MYBPC3 Arg502Trp is the most common and recurrent pathogenic mutation in a diverse primarily European descent HCM cohort, occurring in 2.4% of patients. MYBPC3 Arg502Trp conveys a 340-fold increased risk for HCM by 45 years of age, when more than 50% of carriers have overt disease. HCM prognosis worsens when MYBPC3 Arg502Trp occurs in the setting of another sarcomere protein gene mutation.
| S-EPMC2893345 | biostudies-literature
Project description:Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein’s amino terminal (N’)-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C delta C0-C1f), displayed dilated cardiomyopathy, underscoring the importance of the N’-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N’-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.
2021-03-23 | GSE169340 | GEO
Project description:BackgroundAlthough a heritable basis for sudden cardiac death (SCD) is suggested by the impact of family history on SCD risk, common genetic determinants have been difficult to identify. We hypothesized that a common variant at chromosome 9p21 related to myocardial infarction would influence SCD risk.Methods and resultsThis was a prospective, nested, case-control analysis among individuals of European ancestry enrolled in 6 prospective cohort studies. Study subjects were followed up for development of SCD, and genotypes for rs10757274 were determined for 492 sudden and/or arrhythmic deaths and 1460 controls matched for age, sex, cohort, history of cardiovascular disease, and follow-up time. Conditional logistic regression with fixed-effects meta-analysis assuming an additive model was used to test for associations. When individual study results were combined in the meta-analysis, each increasing copy of the G allele at rs10757274 conferred a significantly elevated age-adjusted odds ratio for SCD of 1.21 (95% confidence interval, 1.04 to 1.40; P=0.01). Controlling for cardiovascular and lifestyle risk factors strengthened these relationships (odds ratio, 1.29 per G-allele copy; 95% confidence interval, 1.09 to 1.53; P=0.003). These results were not materially altered in sensitivity analyses limited to definite SCD, in models that further controlled for the development of interim cardiovascular disease, or when the highly correlated variant rs2383207 was tested.ConclusionsThe major allele of a single-nucleotide polymorphism previously associated with increased risk of coronary artery disease events is associated with increased risk of SCD in individuals of European ancestry. Study of the mechanism underlying this association may improve our understanding of lethal cardiovascular disease.
| S-EPMC2785227 | biostudies-literature
Project description:Decreased expression of cardiac myosin binding protein C (cMyBPC) in the heart has been implicated as a consequence of mutations in cMyBPC that lead to abnormal contractile function at the myofilament level, thereby contributing to the development of hypertrophic cardiomyopathy in humans. It has not been established whether increasing the levels of cMyBPC in the intact heart can improve myofilament and in vivo contractile function and attenuate maladaptive remodeling processes because of reduced levels of cMyBPC.We performed in vivo gene transfer of cMyBPC by direct injection into the myocardium of cMyBPC-deficient (cMyBPC(-/-)) mice, and mechanical experiments were conducted on skinned myocardium isolated from cMyBPC(-/-) hearts 21 days and 20 weeks after gene transfer. Cross-bridge kinetics in skinned myocardium isolated from cMyBPC(-/-) hearts after cMyBPC gene transfer were significantly slower compared with untreated cMyBPC(-/-) myocardium and were comparable to wild-type myocardium and cMyBPC(-/-) myocardium that was reconstituted with recombinant cMyBPC in vitro. cMyBPC content in cMyBPC(-/-) skinned myocardium after in vivo cMyBPC gene transfer or in vitro cMyBPC reconstitution was similar to wild-type levels. In vivo echocardiography studies of cMyBPC(-/-) hearts after cMyBPC gene transfer revealed improved systolic and diastolic contractile function and reductions in left ventricular wall thickness.This proof-of-concept study demonstrates that gene therapy designed to increase expression of cMyBPC in the cMyBPC-deficient myocardium can improve myofilament and in vivo contractile function, suggesting that cMyBPC gene therapy may be a viable approach for treatment of cardiomyopathies because of mutations in cMyBPC.
| S-EPMC4860813 | biostudies-literature
Project description:Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) regulates cardiac contraction through modulation of actomyosin interactions mediated by the protein's amino terminal (N')-region (C0-C2 domains, 358 amino acids). On the other hand, dephosphorylation of cMyBP-C during myocardial injury results in cleavage of the 271 amino acid C0-C1f region and subsequent contractile dysfunction. Yet, our current understanding of amino terminus region of cMyBP-C in the context of regulating thin and thick filament interactions is limited. A novel cardiac-specific transgenic mouse model expressing cMyBP-C, but lacking its C0-C1f region (cMyBP-C∆C0-C1f), displayed dilated cardiomyopathy, underscoring the importance of the N'-region in cMyBP-C. Further exploring the molecular basis for this cardiomyopathy, in vitro studies revealed increased interfilament lattice spacing and rate of tension redevelopment, as well as faster actin-filament sliding velocity within the C-zone of the transgenic sarcomere. Moreover, phosphorylation of the unablated phosphoregulatory sites was increased, likely contributing to normal sarcomere morphology and myoarchitecture. These results led us to hypothesize that restoration of the N'-region of cMyBP-C would return actomyosin interaction to its steady state. Accordingly, we administered recombinant C0-C2 (rC0-C2) to permeabilized cardiomyocytes from transgenic, cMyBP-C null, and human heart failure biopsies, and we found that normal regulation of actomyosin interaction and contractility was restored. Overall, these data provide a unique picture of selective perturbations of the cardiac sarcomere that either lead to injury or adaptation to injury in the myocardium.
| S-EPMC8217138 | biostudies-literature