Cardiac Myosin Binding Protein-C Mutations in Families With Hypertrophic Cardiomyopathy

Page, Stephen P.; Kounas, Stavros P.; Syrris, Petros; Christiansen, Michael; Frank-Hansen, Rune; Andersen, Paal Skytt; Elliott, Perry; McKenna, William J.

doi:10.1161/circgenetics.111.960831

Cited by 136 publications

(73 citation statements)

References 42 publications

(73 reference statements)

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“…26,[28][29][30][31] Extreme hypertrophy was absent in FG+ relatives, and there was less adverse remodeling. Identification of HCM leads to lifestyle modifications, periodic SCD risk stratification, and close clinical follow-up, with the opportunity to implant an ICD for primary prevention and timely referral for septal reduction therapy.…”

Section: Discussionmentioning

confidence: 94%

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Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Velzen

Schinkel

Oldenburg

et al. 2017

Circ Cardiovasc Genet

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Background— MYBPC3 (Myosin-binding protein C) founder mutations account for 35% of hypertrophic cardiomyopathy (HCM) cases in the Netherlands. We compared clinical characteristics and outcome of MYBPC3 founder mutation (FG+) HCM with nonfounder genotype-positive (G+) and genotype-negative (G−) HCM. Methods and Results— The study included 680 subjects: 271 FG+ carriers, 132 G+ probands with HCM, and 277 G− probands with HCM. FG+ carriers included 134 FG+ probands with HCM, 54 FG+ relatives diagnosed with HCM after family screening, 74 FG+/phenotype-negative relatives, and 9 with noncompaction or dilated cardiomyopathy. The clinical phenotype of FG+ and G+ probands with HCM was similar. FG+ and G+ probands were younger with less left ventricular outflow tract obstruction than G− probands, however, had more hypertrophy, and nonsustained ventricular tachycardia. FG+ relatives with HCM had less hypertrophy, smaller left atria, and less systolic and diastolic dysfunction than FG+ probands with HCM. After 8±6 years, cardiovascular mortality in FG+ probands with HCM was similar to G+ HCM (22% versus 14%; log-rank P =0.14), but higher than G− HCM (22% versus 6%; log-rank P <0.001) and FG+ relatives with HCM (22% versus 4%; P =0.009). Cardiac events were absent in FG+/phenotype-negative relatives; subtle HCM developed in 11% during 6 years of follow-up. Conclusions— Clinical phenotype and outcome of FG+ HCM was similar to G+ HCM but worse than G− HCM and FG+ HCM diagnosed in the context of family screening. These findings indicate the need for more intensive follow-up of FG+ and G+ HCM versus G− HCM and FG+ HCM in relatives.

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Section: Discussionmentioning

confidence: 94%

“…Because of the known age-related penetrance in HCM, 29 longterm follow-up of FG+/Ph− subjects is recommended. 13,20,35 The interval at which clinical evaluation should be repeated is subject to debate.…”

Section: Fg+/ph− Individualsmentioning

confidence: 99%

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Velzen

Schinkel

Oldenburg

et al. 2017

Circ Cardiovasc Genet

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“…Compared with the ␤-MHC, genetic mutations in the ELC are rare but they are also associated with malignant outcomes (3,13,17,29,42). In this report we followed up on our structural observations associated with the alanine to glycine mutation occurring at residue 57 of the human ventricular ELC shown to cause hypertrophic cardiomyopathy and SCD (29).…”

Section: Discussionmentioning

confidence: 99%

Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

Kazmierczak

Paulino

Huang

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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(alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G-or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca 2ϩ sensitivity of force (⌬pCa50 Х 0.1) and an ϳ1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca 2ϩ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling. myosin essential light chain; hypertrophic cardiomyopathy; Ca 2ϩ sensitivity of contraction; echocardiography; pressure-volume loops THE BEATING OF THE HEART DEPENDS on ATP-controlled synchronous interactions between two major contractile proteins; myosin and actin (15). The myosin cross bridges are the molecular motors of the heart, which bind and hydrolyze Mg-ATP and cyclically attach and dissociate from actin-tropomyosin (Tm)-troponin (Tn) thin filaments in a Ca 2ϩ -dependent manner. The cycle of Ca 2ϩ fluxes regulate the coupling between excitation and contraction and permit the highly synchronized action of cardiac sarcomeres causing the heart to contract (systole) or relax (diastole) (20). The two key components of the myosin cross bridge include the motor domain, consisting of the ATP and actin binding sites, and the neck domain also called the lever arm, which is structurally supported by two types of myosin light chains, the essential (ELC) and the regulatory (RLC) light chains (44). Attached to their respective IQ motifs on the myosin heavy chain (MHC), both light chains inherently participate in all biochemical steps of the acto-myosin cycle and execution of the power stroke (52). As components of the neck region of myosin, both ELC and RL...

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“…HCM is characterized by LV hypertrophy (i.e., increased LV wall thickness [LVWT]), myocyte enlargement and disarray, and increased myocardial fibrosis, but the severity of these manifestations and associated symptoms vary among patients. Recent studies have shown more severe LV hypertrophy (8), disease progression (9,10), and adverse outcomes, including sudden cardiac death (11,12), in men than women with HCM, information that implicates a role for genetic modifiers in disease expression. Using 5′RNA-Seq, we identified 92 genes with altered 5′ start-site usage in HCM.…”

Section: Introductionmentioning

confidence: 99%

5′RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy

et al. 2014

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The transcriptome is subject to multiple changes during pathogenesis, including the use of alternate 5′ startsites that can affect transcription levels and output. Current RNA sequencing techniques can assess mRNA levels, but do not robustly detect changes in 5′ start-site use. Here, we developed a transcriptome sequencing strategy that detects genome-wide changes in start-site usage (5′RNA-Seq) and applied this methodology to identify regulatory events that occur in hypertrophic cardiomyopathy (HCM). Compared with transcripts from WT mice, 92 genes had altered start-site usage in a mouse model of HCM, including four-and-a-half LIM domains protein 1 (Fhl1). HCM-induced altered transcriptional regulation of Fhl1 resulted in robust myocyte expression of a distinct protein isoform, a response that was conserved in humans with genetic or acquired cardiomyopathies. Genetic ablation of Fhl1 in HCM mice was deleterious, which suggests that Fhl1 transcriptional changes provide salutary effects on stressed myocytes in this disease. Because Fhl1 is a chromosome X-encoded gene, stress-induced changes in its transcription may contribute to gender differences in the clinical severity of HCM. Our findings indicate that 5′RNA-Seq has the potential to identify genomewide changes in 5′ start-site usage that are associated with pathogenic phenotypes.

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Cardiac Myosin Binding Protein-C Mutations in Families With Hypertrophic Cardiomyopathy

Cited by 136 publications

References 42 publications

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation

Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy

5′RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy

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