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Myosin Heavy Chain Converter Domain Mutations Drive Early-Stage Changes in Extracellular Matrix Dynamics in Hypertrophic Cardiomyopathy.

ABSTRACT: More than 60% of hypertrophic cardiomyopathy (HCM)-causing mutations are found in the gene loci encoding cardiac myosin-associated proteins including myosin heavy chain (MHC) and myosin binding protein C (MyBP-C). Moreover, patients with more than one independent HCM mutation may be at increased risk for more severe disease expression and adverse outcomes. However detailed mechanistic understanding, especially at early stages of disease progression, is limited. To identify early-stage HCM triggers, we generated single (MYH7 c.2167C > T [R723C] with a known pathogenic significance in the MHC converter domain) and double (MYH7 c.2167C > T [R723C]; MYH6 c.2173C > T [R725C] with unknown significance) myosin gene mutations in human induced pluripotent stem cells (hiPSCs) using a base-editing strategy. Cardiomyocytes (CMs) derived from hiPSCs with either single or double mutation exhibited phenotypic characteristics consistent with later-stage HCM including hypertrophy, multinucleation, altered calcium handling, metabolism, and arrhythmia. We then probed mutant CMs at time points prior to the detection of known HCM characteristics. We found MYH7/MYH6 dual mutation dysregulated extracellular matrix (ECM) remodeling, altered integrin expression, and interrupted cell-ECM adhesion by limiting the formation of focal adhesions. These results point to a new phenotypic feature of early-stage HCM and reveal novel therapeutic avenues aimed to delay or prohibit disease onset.

SUBMITTER: Hsieh J

PROVIDER: S-EPMC9245526 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Biophysical properties of human β-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy.

Project description:Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is an important cause of arrhythmias and heart failure. Clinically, HCM is characterized as causing hypercontractility, and therapies are aimed toward controlling the hyperactive physiology. Mutations in the β-cardiac myosin comprise ~40% of genetic mutations associated with HCM, and the converter domain of myosin is a hotspot for HCM-causing mutations; however, the underlying primary effects of these mutations on myosin's biomechanical function remain elusive. We hypothesize that these mutations affect the biomechanical properties of myosin, such as increasing its intrinsic force and/or its duty ratio and therefore the ensemble force of the sarcomere. Using recombinant human β-cardiac myosin, we characterize the molecular effects of three severe HCM-causing converter domain mutations: R719W, R723G, and G741R. Contrary to our hypothesis, the intrinsic forces of R719W and R723G mutant myosins are decreased compared to wild type and unchanged for G741R. Actin and regulated thin filament gliding velocities are ~15% faster for R719W and R723G myosins, whereas there is no change in velocity for G741R. Adenosine triphosphatase activities and the load-dependent velocity change profiles of all three mutant proteins are very similar to those of wild type. These results indicate that the net biomechanical properties of human β-cardiac myosin carrying these converter domain mutations are very similar to those of wild type or are even slightly hypocontractile, leading us to consider an alternative mechanism for the clinically observed hypercontractility. Future work includes how these mutations affect protein interactions within the sarcomere that increase the availability of myosin heads participating in force production.

| S-EPMC5302870 | biostudies-literature

Unexpectedly low mutation rates in beta-myosin heavy chain and cardiac myosin binding protein genes in Italian patients with hypertrophic cardiomyopathy.

Project description:Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease. Fourteen sarcomeric and sarcomere-related genes have been implicated in HCM etiology, those encoding ?-myosin heavy chain (MYH7) and cardiac myosin binding protein C (MYBPC3) reported as the most frequently mutated: in fact, these account for around 50% of all cases related to sarcomeric gene mutations, which are collectively responsible for approximately 70% of all HCM cases. Here, we used denaturing high-performance liquid chromatography followed by bidirectional sequencing to screen the coding regions of MYH7 and MYBPC3 in a cohort (n?=?125) of Italian patients presenting with HCM. We found 6 MHY7 mutations in 9/125 patients and 18 MYBPC3 mutations in 19/125 patients. Of the three novel MYH7 mutations found, two were missense, and one was a silent mutation; of the eight novel MYBPC3 mutations, one was a substitution, three were stop codons, and four were missense mutations. Thus, our cohort of Italian HCM patients did not harbor the high frequency of mutations usually found in MYH7 and MYBPC3. This finding, coupled to the clinical diversity of our cohort, emphasizes the complexity of HCM and the need for more inclusive investigative approaches in order to fully understand the pathogenesis of this disease.

| S-EPMC3229838 | biostudies-literature

5'RNA-seq analysis of hypertrophic cardiomyopathy (HCM) in mice that carry a human missence mutation in the myosin heavy chain

Project description:We developed a 5'RNA-seq methodology to concurrently assess gene expression and start-site usage changes. We applied this methodology to study hypertrophic cardiomyopathy in mice harboring a human deleterious mutation. 5'RNA-seq analysis of transcriptomes from mouse hearts with or without hypertrophic cardiomyopathy. Biological replicates were pooled into a single sequencing run. 5'RNA-seq methodology consists of enhanced sequencing of 5' ends and computational assessment of changes at start-sites of genes.

2013-11-05 | E-GEOD-52038 | biostudies-arrayexpress

Functional effects of the hypertrophic cardiomyopathy R403Q mutation are different in an alpha- or beta-myosin heavy chain backbone.

Project description:The R403Q mutation in the beta-myosin heavy chain (MHC) was the first mutation to be linked to familial hypertrophic cardiomyopathy (FHC), a primary disease of heart muscle. The initial studies with R403Q myosin, isolated from biopsies of patients, showed a large decrease in myosin motor function, leading to the hypothesis that hypertrophy was a compensatory response. The introduction of the mouse model for FHC (the mouse expresses predominantly alpha-MHC as opposed to the beta-isoform in larger mammals) created a new paradigm for FHC based on finding enhanced motor function for R403Q alpha-MHC. To help resolve these conflicting mechanisms, we used a transgenic mouse model in which the endogenous alpha-MHC was largely replaced with transgenically encoded beta-MHC. A His(6) tag was cloned at the N terminus of the alpha-and beta-MHC to facilitate protein isolation by Ni(2+)-chelating chromatography. Characterization of the R403Q alpha-MHC by the in vitro motility assay showed a 30-40% increase in actin filament velocity compared with wild type, consistent with published studies. In contrast, the R403Q mutation in a beta-MHC backbone showed no enhancement in velocity. Cleavage of the His-tagged myosin by chymotrypsin made it possible to isolate homogeneous myosin subfragment 1 (S1), uncontaminated by endogenous myosin. We find that the actin-activated MgATPase activity for R403Q alpha-S1 is approximately 30% higher than for wild type, whereas the enzymatic activity for R403Q beta-S1 is reduced by approximately 10%. Thus, the functional consequences of the mutation are fundamentally changed depending upon the context of the cardiac MHC isoform.

| S-EPMC2459289 | biostudies-literature

Phenotype and prognostic correlations of the converter region mutations affecting the β myosin heavy chain.

Project description:ObjectivesThe prognostic value of genetic studies in cardiomyopathies is still controversial. Our objective was to evaluate the outcome of patients with cardiomyopathy with mutations in the converter domain of β myosin heavy chain (MYH7).MethodsClinical characteristics and survival of 117 affected members with mutations in the converter domain of MYH7 were compared with 409 patients described in the literature with mutations in the same region.ResultsTwenty-five mutations were evaluated (9 in our families including 3 novel (Ile730Asn, Asp717Gly and Arg719Pro)). Clinical diagnoses were hypertrophic (n=407), dilated (n=15), non-compaction (n=4) and restrictive (n=5) cardiomyopathies, unspecified cardiomyopathy (n=11), sudden death (n=50) and 35 healthy carriers. One hundred eighty-four had events (cardiovascular death or transplant). Median event-free survival was 50±2 years in our patients and 53±3 years in the literature (p=0.27). There were significant differences in the outcome between mutation: Ile736Thr had fewer events than other mutations in the region (p=0.01), while Arg719Gln (p<0.01) had reduced event-free survival.ConclusionsMutations in the converter region are generally associated with adverse prognosis although there are differences between mutations. The identification of a mutation in this particular region provides important prognostic information that should be considered in the clinical management of affected patients.

| S-EPMC4484257 | biostudies-literature

5'RNA-seq analysis of hypertrophic cardiomyopathy (HCM) in mice that carry a human missence mutation in the myosin heavy chain

2013-11-05 | GSE52038 | GEO

Activated fibroblasts drive cellular interactions in end-stage pediatric hypertrophic cardiomyopathy.

Project description:Hypertrophic cardiomyopathy (HCM) is a relatively rare but debilitating diagnosis in the pediatric population and patients with end-stage HCM require heart transplantation. In this study, we performed single-nucleus RNA sequencing on pediatric HCM and control myocardium. We identified distinct underling cellular processes in pediatric, end-stage HCM in cardiomyocytes, fibroblasts, endothelial cells, and myeloid cells, compared to controls. Pediatric HCM was enriched in cardiomyocytes exhibiting "stressed" myocardium gene signatures and underlying pathways associated with cardiac hypertrophy. Cardiac fibroblasts exhibited clear activation signatures and heightened downstream processes associated with fibrosis, more so than adult counterparts. There was notable depletion of tissue-resident macrophages, and increased vascular remodeling in endothelial cells. Our analysis provides the first single nuclei analysis focused on end-stage pediatric HCM.

| S-EPMC10862753 | biostudies-literature

Genetic variant affecting the myosin light chain 2 related to familial hypertrophic cardiomyopathy.

Project description:Familial hypertrophic cardiomyopathy (FHCM) is a genetic disease characterized by left ventricle (LV) or interventricular septum hypertrophy. FHCM is a common heart disease (affecting 1 out of 500 individuals) associated with genetic variants in genes related to the sarcomere, including the MYL2 (myosin light chain 2) gene that is affected in 1 to 3% of the cases. As described in this report, the genetic mutation p.Gly87Ala, rs 397516399 in the MYL2 gene is likely pathogenic. Reported here is the case of a 37-year-old Colombian man with asymmetric septal hypertrophic cardiomyopathy and ventricular tachycardia. The man had progressive symptomatology, a family history of FHCM with a dominant inheritance pattern, a mother and 2 brothers with FHCM, and 2 brothers who died suddenly before the age of 35. A molecular panel of 17 genes for hypertrophic cardiomyopathy identified a heterozygous variant, p.Gly87Ala, of the MYL2 gene. This variant can be found in Ensembl, dbSNP, and ClinVar, where it has conflicting interpretations: it either has an uncertain significance or it is likely pathogenic. This is the first report of a Colombian case of FHCM secondary to a mutation in the MYL2 gene, highlighting the importance of molecular diagnosis, genetic counseling, and bioinformatic analysis in these patients.

| S-EPMC7586884 | biostudies-literature

The cardiac myosin heavy chain Arg-403-->Gln mutation that causes hypertrophic cardiomyopathy does not affect the actin- or ATP-binding capacities of two size-limited recombinant myosin heavy chain fragments.

Project description:Our aim was to investigate the potential functional consequences of myosin heavy chain (MHC) mutations identified in patients with familial hypertrophic cardiomyopathy. We observed the presence of a mutated beta-MHC mRNA in a formalin-fixed paraffin-embedded myocardial tissue of a proband from family A, which Geisterfer-Lowrance et al. [Geisterfer-Lowrance, Kass, Tanigawa, Vosberg, McKenna, Seidman and Seidman (1990) Cell 62, 999-1006] identified as carrying the Arg-403 to Gln mutation. Recombinant DNA methods were then used to obtain size-limited, soluble and undenatured fragments of mutated myosin subfragment 1 focused around the 403 mutation. The present analysis indicated that the 403 mutation did not quantitatively alter the actin- or ATP-binding capacities of two 246-residue or 524-residue-long recombinant MHC fragments containing this mutation. The absence of any apparent impact of the 403 mutation in the recombinant MHC fragments on interactions between actin and ATP is discussed in relation to numerous biochemical and structural reports which demonstrate the crucial role of the central MHC segment, where the 403 mutation occurs, in myosin functions.

| S-EPMC1136527 | biostudies-other

β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

Project description:RationaleApproximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family.ObjectiveTo characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice.Methods and resultsUnlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling.ConclusionsThe VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations.

| S-EPMC4086907 | biostudies-literature

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