Transgenic Rabbits Expressing Mutant Essential Light Chain do not Develop Hypertrophic Cardiomyopathy

2002 ◽  
Vol 34 (7) ◽  
pp. 873-882 ◽  
Author(s):  
Jeanne James ◽  
Yan Zhang ◽  
Kathy Wright ◽  
Sra Witt ◽  
Elizabeth Glascock ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Essential Light Chain ◽  
Transgenic Rabbits

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

2013 ◽  
Vol 305 (4) ◽  
pp. H575-H589 ◽  
Author(s):  
Katarzyna Kazmierczak ◽  
Ellena C. Paulino ◽  
Wenrui Huang ◽  
Priya Muthu ◽  
Jingsheng Liang ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Left Ventricular ◽  
Compensatory Hypertrophy ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Heart Weight ◽  
Myocardial Stiffness ◽  
Essential Light Chain

The functional consequences of the familial hypertrophic cardiomyopathy A57G (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 Ca2+ sensitivity of force (ΔpCa50 ≅ 0.1) and an ∼1.3-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 Ca2+ 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.

scholarly journals A Novel Myosin Essential Light Chain Mutation Causes Hypertrophic Cardiomyopathy with Late Onset and Low Expressivity

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Paal Skytt Andersen ◽  
Paula Louise Hedley ◽  
Stephen P. Page ◽  
Petros Syrris ◽  
Johanna Catharina Moolman-Smook ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Late Onset ◽  
Large Family ◽  
Left Ventricular ◽  
Cascade Screening ◽  
Essential Light Chain ◽  
Mutation Carriers ◽  
Genes Encoding ◽  
The Mean

Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes encoding sarcomere proteins. Mutations inMYL3, encoding the essential light chain of myosin, are rare and have been associated with sudden death. Both recessive and dominant patterns of inheritance have been suggested. We studied a large family with a 38-year-old asymptomatic HCM-affected male referred because of a murmur. The patient had HCM with left ventricular hypertrophy (max WT 21 mm), a resting left ventricular outflow gradient of 36 mm Hg, and left atrial dilation (54 mm). Genotyping revealed heterozygosity for a novel missense mutation, p.V79I, inMYL3. The mutation was not found in 300 controls, and the patient had no mutations in 10 sarcomere genes. Cascade screening revealed a further nine heterozygote mutation carriers, three of whom had ECG and/or echocardiographic abnormalities but did not fulfil diagnostic criteria for HCM. The penetrance, if we consider this borderline HCM the phenotype of the p.V79I mutation, was 40%, but the mean age of the nonpenetrant mutation carriers is 15, while the mean age of the penetrant mutation carriers is 47. The mutation affects a conserved valine replacing it with a larger isoleucine residue in the region of contact between the light chain and the myosin lever arm. In conclusion,MYL3mutations can present with low expressivity and late onset.

E22K mutation of RLC that causes familial hypertrophic cardiomyopathy in heterozygous mouse myocardium: effect on cross-bridge kinetics

2006 ◽  
Vol 291 (5) ◽  
pp. H2098-H2106 ◽  
Author(s):  
D. Dumka ◽  
J. Talent ◽  
I. Akopova ◽  
G. Guzman ◽  
D. Szczesna-Cordary ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Time Resolved ◽  
Essential Light Chain ◽  
Cross Bridge ◽  
The Difference ◽  
Cross Bridges ◽  
The Times

Familial hypertrophic cardiomyopathy is a disease characterized by left ventricular and/or septal hypertrophy and myofibrillar disarray. It is caused by mutations in sarcomeric proteins, including the ventricular isoform of myosin regulatory light chain (RLC). The E22K mutation is located in the RLC Ca2+-binding site. We have studied transgenic (Tg) mouse cardiac myofibrils during single-turnover contraction to examine the influence of E22K mutation on 1) dissociation time (τ1) of myosin heads from thin filaments, 2) rebinding time (τ2) of the cross bridges to actin, and 3) dissociation time (τ3) of ADP from the active site of myosin. τ1 was determined from the increase in the rate of rotation of actin monomer to which a cross bridge was bound. τ2 was determined from the rate of anisotropy change of the recombinant essential light chain of myosin labeled with rhodamine exchanged for native light chain (LC1) in the cardiac myofibrils. τ3 was determined from anisotropy of muscle preloaded with a stoichiometric amount of fluorescent ADP. Cross bridges were induced to undergo a single detachment-attachment cycle by a precise delivery of stoichiometric ATP from a caged precursor. The times were measured in Tg-mutated (Tg-m) heart myofibrils overexpressing the E22K mutation of human cardiac RLC. Tg wild-type (Tg-wt) and non-Tg muscles acted as controls. τ1 was statistically greater in Tg-m than in controls. τ2 was shorter in Tg-m than in non-Tg, but the same as in Tg-wt. τ3 was the same in Tg-m and controls. To determine whether the difference in τ1 was due to intrinsic difference in myosin, we estimated binding of Tg-m and Tg-wt myosin to fluorescently labeled actin by measuring fluorescent lifetime and time-resolved anisotropy. No difference in binding was observed. These results suggest that the E22K mutation has no effect on mechanical properties of cross bridges. The slight increase in τ1 was probably caused by myofibrillar disarray. The decrease in τ2 of Tg hearts was probably caused by replacement of the mouse RLC for the human isoform in the Tg mice.

scholarly journals Ablation of the N terminus of cardiac essential light chain promotes the super‐relaxed state of myosin and counteracts hypercontractility in hypertrophic cardiomyopathy mutant mice

FEBS Journal ◽  
2020 ◽  
Vol 287 (18) ◽  
pp. 3989-4004 ◽  
Author(s):  
Yoel H. Sitbon ◽  
Katarzyna Kazmierczak ◽  
Jingsheng Liang ◽  
Sunil Yadav ◽  
Melanie Veerasammy ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Light Chain ◽  
Mutant Mice ◽  
Essential Light Chain ◽  
N Terminus

Functional regions in the essential light chain of smooth muscle myosin as revealed by the mutagenesis approach

2000 ◽  
Vol 267 (20) ◽  
pp. 6151-6157 ◽  
Author(s):  
Sophie Quevillon-Chéruel ◽  
Chantal Janmot ◽  
Muriel Nozais ◽  
Anne-Marie Lompré ◽  
Jean-Jacques Béchet
Keyword(s):  
Smooth Muscle ◽  
Light Chain ◽  
Smooth Muscle Myosin ◽  
Essential Light Chain ◽  
Functional Regions ◽  
Muscle Myosin

scholarly journals Orientation of the Essential Light Chain Region of Myosin in Relaxed, Active, and Rigor Muscle

2008 ◽  
Vol 95 (8) ◽  
pp. 3882-3891 ◽  
Author(s):  
Andrea C. Knowles ◽  
Roisean E. Ferguson ◽  
Birgit D. Brandmeier ◽  
Yin-Biao Sun ◽  
David R. Trentham ◽  
...  
Keyword(s):  
Light Chain ◽  
Essential Light Chain
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