Cardiomyopathy Mutations in the Tail of β-Cardiac Myosin Modify the Coiled-coil Structure and Affect Integration into Thick Filaments in Muscle Sarcomeres in Adult Cardiomyocytes

Wolny, Marcin; Colegrave, Melanie; Colman, Lucy; White, Edward; Knight, Peter J.; Peckham, Michelle

doi:10.1074/jbc.m113.513291

Cited by 38 publications

(43 citation statements)

References 55 publications

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“…15 The effect of the N1327T mutation, in particular, on the structure and function of the beta-cardiac myosin protein has been shown to be more severe than the effects of other HCM-causing mutations at MYH7. 16 In line with previous evidence on the great variability of phenotypic expression of the disease state in families affected by HCM8, we found that the presence of the responsible genetic mutation was not always associated with cardiac hypertrophy in this family. While the affected son was diagnosed with HCM at 6 months of age, the father and brother, both of whom also possessed the mutant gene, had normal echocardiograms at last evaluation (age 36 yr and 5 yr, respectively).…”

Section: Discussionsupporting

confidence: 91%

A novel mutation of the MYH7 gene in a patient with hypertrophic cardiomyopathy

Goel¹,

Huddleston²,

Fiore³

2018

Turk J Pediatr

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Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by asymmetric cardiac hypertrophy due to inherited mutations in genes that encode sarcomeric proteins. MYH7, which encodes β-myosin heavy chain, is among the most commonly mutated genes in patients affected by HCM. We aimed to identify the specific mutation responsible for HCM in a sixmonth old Caucasian patient. NextGen DNA sequencing revealed a novel p.Ala1328Thr (A1328T) mutation of MYH7 in the affected patient as well as his asymptomatic father and asymptomatic brother. The clinical details of this mutation are described for the first time in this report. The genetic variant affects a residue that is highly conserved across species. Theoretical analysis suggests that A1328T is very likely deleterious to β-myosin heavy chain protein structure and function. Furthermore, this novel mutation was not observed with any significant frequency in approximately 6,500 healthy individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, underlining the potential pathogenicity of this variant.

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Section: Discussionsupporting

confidence: 91%

A novel mutation of the MYH7 gene in a patient with hypertrophic cardiomyopathy

Goel¹,

Huddleston²,

Fiore³

2018

Turk J Pediatr

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“…4 and Supplemental Table S3). It is also plausible that alterations in the α-MHC tail cause reduced power, as mutations in the tail of homolog β-MHC reportedly distort helicity of the coiled-coil region (42). …”

Section: Discussionmentioning

confidence: 99%

Impact of MYH6 variants in hypoplastic left heart syndrome

Tomita‐Mitchell

Stamm

Mahnke

et al. 2016

Physiological Genomics

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Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P < 1 × 10−5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P < 1 × 10−2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the β-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P < 1 × 10−3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P < 1 × 10−2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications.

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“…Furthermore, our laboratory previously showed that LMM is the minimum required domain for incorporation into thick filaments in cultured myotubes, while S1 is dispensable (39). Moreover, mutations in LMM caused poor incorporation into thick filaments, indicating the importance of this domain for proper targeting to thick filaments (59). Thus, myosin exchange between myofibrils and nonmyofibrillar cytosol may be largely dependent on LMM.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of myosin replacement in skeletal muscle cells

Ojima

Ichimura

Yasukawa

et al. 2015

American Journal of Physiology-Cell Physiology

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Highly organized thick filaments in skeletal muscle cells are formed from ~300 myosin molecules. Each thick-filament-associated myosin molecule is thought to be constantly exchanged. However, the mechanism of myosin replacement remains unclear, as does the source of myosin for substitution. Here, we investigated the dynamics of myosin exchange in the myofibrils of cultured myotubes by fluorescent recovery after photobleaching and found that myofibrillar myosin is actively replaced with an exchange half-life of ~3 h. Myosin replacement was not disrupted by the absence of the microtubule system or by actomyosin interactions, suggesting that known cytoskeletal systems are dispensable for myosin substitution. Intriguingly, myosin replacement was independent of myosin binding protein C, which links myosin molecules together to form thick filaments. This implies that an individual myosin molecule rather than a thick filament functions as an exchange unit. Furthermore, the myosin substitution rate was decreased by the inhibition of protein synthesis, suggesting that newly synthesized myosin, as well as preexisting cytosolic myosin, contributes to myosin replacement in myofibrils. Notably, incorporation and release of myosin occurred simultaneously in myofibrils, but rapid myosin release from myofibrils was observed without protein synthesis. Collectively, our results indicate that myosin shuttles between myofibrils and the nonmyofibrillar cytosol to maintain a dynamic equilibrium in skeletal muscle cells.

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Cardiomyopathy Mutations in the Tail of β-Cardiac Myosin Modify the Coiled-coil Structure and Affect Integration into Thick Filaments in Muscle Sarcomeres in Adult Cardiomyocytes

Cited by 38 publications

References 55 publications

A novel mutation of the MYH7 gene in a patient with hypertrophic cardiomyopathy

A novel mutation of the MYH7 gene in a patient with hypertrophic cardiomyopathy

Impact of MYH6 variants in hypoplastic left heart syndrome

Dynamics of myosin replacement in skeletal muscle cells

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