Different expressivity of a ventricular essential myosin light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy

Lee, Won‐Ha; Hwang, Tae Hong; Kimura, Akinori; Park, Seung Woo; Satoh, Manatsu; Nishi, Hirofumi; Harada, Haruhito; Toyama, Junji; Park, Jeong-Euy

doi:10.1067/mhj.2001.112487

Cited by 49 publications

(44 citation statements)

References 20 publications

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“…As demonstrated by Lee et al (29), occurrences of SCD were reported in family members carrying the A57G mutation. However, it is not uncommon that hypertrophic cardiomyopathy patients have normal systolic function and yet may die suddenly.…”

Section: Mutant-induced Ventricular Remodeling In Tg-a57g Micementioning

confidence: 79%

“…Research interests in the ELC of myosin as a potential regulator of cardiac muscle contraction have been high since the discovery of several FHC-associated mutations in the MYL3 gene that encodes for the ventricular myosin ELC (13,22,29,37,41,43,45). Compared with the ␤-MHC, genetic mutations in the ELC are rare but they are also associated with malignant outcomes (3,13,17,29,42).…”

Section: Discussionmentioning

confidence: 99%

“…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). Our previous study demonstrated a mutation-induced decrease in the interfilament lattice spacing and increased rigor stiffness in skinned papillary muscles from Tg-A57G mice compared with Tg-WT controls (40).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, FHC has been considered the leading cause of SCD in the young, especially in athletes (33,47). Compared with the ␤-MHC or cardiac myosin binding protein-C (cMyBP-C), FHC-linked mutations in the ventricular ELC are rare, but they are also associated with SCD (13,22,29,37,41,43,45). In this report, we focus on the A57G (alanine to glycine) mutation implicated in malignant FHC outcomes (29).…”

mentioning

confidence: 99%

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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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Section: Mutant-induced Ventricular Remodeling In Tg-a57g Micementioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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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“…Mutations in myosin regulatory or essential light chains rarely cause HCM although the limited number of families reported with these gene defects has hindered correlation of genotype and phenotype [28]. Distinctive cardiac morphologies have however been reported with some mutations (ventricular regulatory myosin Ala13Thr and Glu22Lys, and myosin essential light chain Met149Val), including predominance of midventricular hypertrophy that resulted in a systolic mid cavity obliteration (hour glass morphology) [29]. More typical asymmetric hypertrophy also occurs from mutations in these disease genes.…”

Section: Hypertrophic Cardiomyopathy: the Clinical Diseasementioning

confidence: 99%

Hypertrophic cardiomyopathy: from gene defect to clinical disease

2003

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Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM, and the role of both environmental and genetic modifying factors. Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function, and will therefore provide new avenues for treating cardiovascular disease in man.

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Genetic Basis and Genotype‐Phenotype Relationships in Familial Hypertrophic Cardiomyopathy

Hagège¹,

Schwartz²,

Desnos³

et al. 2004

Diagnosis and Management of Hypertrophic Cardiomyopathy

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Different expressivity of a ventricular essential myosin light chain gene Ala57Gly mutation in familial hypertrophic cardiomyopathy

Cited by 49 publications

References 20 publications

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

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

Hypertrophic cardiomyopathy: from gene defect to clinical disease

Genetic Basis and Genotype‐Phenotype Relationships in Familial Hypertrophic Cardiomyopathy

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