scholarly journals A Type 2 Ryanodine Receptor Variant in the Helical Domain 2 Associated with an Impairment of the Adrenergic Response

2021 ◽  
Vol 11 (6) ◽  
pp. 579
Author(s):  
Malorie Blancard ◽  
Zahia Touat-Hamici ◽  
Yuriana Aguilar-Sanchez ◽  
Liheng Yin ◽  
Guy Vaksmann ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Missense Variant ◽  
Polymorphic Ventricular Tachycardia ◽  
Loss Of Function ◽  
Adrenergic Stimulation ◽  
Normal Response ◽  
Atypical Form ◽  
Helical Domain ◽  
Adrenergic Response

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is triggered by exercise or acute emotion in patients with normal resting electrocardiogram. The major disease-causing gene is RYR2, encoding the cardiac ryanodine receptor (RyR2). We report a novel RYR2 variant, p.Asp3291Val, outside the four CPVT mutation hotspots, in three CPVT families with numerous sudden deaths. This missense variant was first identified in a four-generation family, where eight sudden cardiac deaths occurred before the age of 30 in the context of adrenergic stress. All affected subjects harbored at least one copy of the RYR2 variant. Three affected sisters were homozygous for the variant. The same variant was found in two additional CPVT families. It is located in the helical domain 2 and changes a negatively charged amino acid widely conserved through evolution. Functional analysis of D3291V channels revealed a normal response to cytosolic Ca2+, a markedly reduced luminal Ca2+ sensitivity and, more importantly, an absence of normal response to 8-bromo-cAMP and forskolin stimulation in both transfected HEK293 and HL-1 cells. Our data support that the D3291V-RyR2 is a loss-of-function RyR2 variant responsible for an atypical form of CPVT inducing a mild dysfunction in basal conditions but leading potentially to fatal events through its unresponsiveness to adrenergic stimulation.

scholarly journals Phosphorylation of the ryanodine receptor 2 at serine 2030 is required for a complete β-adrenergic response

2018 ◽  
Vol 151 (2) ◽  
pp. 131-145 ◽  
Author(s):  
Duilio M. Potenza ◽  
Radoslav Janicek ◽  
Miguel Fernandez-Tenorio ◽  
Emmanuel Camors ◽  
Roberto Ramos-Mondragón ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Cardiac Contractility ◽  
Phosphorylation Site ◽  
Adrenergic Stimulation ◽  
Permeabilized Cells ◽  
Whole Cell Patch Clamp ◽  
Adrenergic Response ◽  
Pump Activity ◽  
Ryr2 Channel ◽  
A Site

During physical exercise or stress, the sympathetic system stimulates cardiac contractility via β-adrenergic receptor (β-AR) activation, resulting in protein kinase A (PKA)–mediated phosphorylation of the cardiac ryanodine receptor RyR2. PKA-dependent “hyperphosphorylation” of the RyR2 channel has been proposed as a major impairment that contributes to progression of heart failure. However, the sites of PKA phosphorylation and their phosphorylation status in cardiac diseases are not well defined. Among the known RyR2 phosphorylation sites, serine 2030 (S2030) remains highly controversial as a site of functional impact. We examined the contribution of RyR2-S2030 to Ca2+ signaling and excitation–contraction coupling (ECC) in a transgenic mouse with an ablated RyR2-S2030 phosphorylation site (RyR2-S2030A+/+). We assessed ECC gain by using whole-cell patch–clamp recordings and confocal Ca2+ imaging during β-ARs stimulation with isoproterenol (Iso) and consistent SR Ca2+ loading and L-type Ca2+ current (ICa) triggering. Under these conditions, ECC gain is diminished in mutant compared with WT cardiomyocytes. Resting Ca2+ spark frequency (CaSpF) with Iso is also reduced by mutation of S2030. In permeabilized cells, when SR Ca2+ pump activity is kept constant (using 2D12 antibody against phospholamban), cAMP does not change CaSpF in S2030A+/+ myocytes. Using Ca2+ spark recovery analysis, we found that mutant RyR Ca2+ sensitivity is not enhanced by Iso application, contrary to WT RyRs. Furthermore, ablation of RyR2-S2030 prevents acceleration of Ca2+ waves and increases latency to the first spontaneous Ca2+ release after a train of stimulations during Iso treatment. Together, these results suggest that phosphorylation at S2030 may represent an important step in the modulation of RyR2 activity during β-adrenergic stimulation and a potential target for the development of new antiarrhythmic drugs.

scholarly journals Case Report: An Atypical Form of Familial Partial Lipodystrophy Type 2 Due to Mutation in the Rod Domain of Lamin A/C

2021 ◽  
Vol 12 ◽  
Author(s):  
Carolina Cecchetti ◽  
M. Rosaria D’Apice ◽  
Elena Morini ◽  
Giuseppe Novelli ◽  
Carmine Pizzi ◽  
...  
Keyword(s):  
Genetic Diagnosis ◽  
Coiled Coil ◽  
Missense Variant ◽  
Lamin A ◽  
Metabolic Complications ◽  
Partial Lipodystrophy ◽  
Atypical Form ◽  
Amino Terminal ◽  
Familial Partial Lipodystrophy

PurposeFamilial partial lipodystrophy type 2 (FPLD2) patients generally develop a wide variety of severe metabolic complications. However, they are not usually affected by primary cardiomyopathy and conduction system disturbances, although a few cases of FPLD2 and cardiomyopathy have been reported in the literature. These were all due to amino-terminal heterozygous lamin A/C mutations, which are considered as new forms of overlapping syndromes.Methods and ResultsHere we report the identification of a female patient with FPLD2 due to a heterozygous missense variant c.604G>A in the exon 3 of the LMNA gene, leading to amino acid substitution (p.Glu202Lys) in the central alpha-helical rod domain of lamin A/C with a high propensity to form coiled-coil dimers. The patient’s cardiac evaluations that followed the genetic diagnosis revealed cardiac rhythm disturbances which were promptly treated pharmacologically.ConclusionsThis report supports the idea that there are “atypical forms” of FPLD2 with cardiomyopathy, especially when a pathogenic variant affects the lamin A/C head or alpha-helical rod domain. It also highlights how increased understanding of the genotype-phenotype correlation could help clinicians to schedule personalized monitoring of the lipodystrophic patient, in order to prevent uncommon but possible devastating manifestations, including arrhythmias and sudden death.

Complex atrial arrhythmias as first manifestation of catecholaminergic polymorphic ventricular tachycardia: an unusual course in a patient with a new mutation in ryanodine receptor type 2 gene

2013 ◽  
Vol 24 (4) ◽  
pp. 741-744 ◽  
Author(s):  
Wolfgang Lawrenz ◽  
Otto N. Krogmann ◽  
Marcus Wieczorek
Keyword(s):  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Sinus Node ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Receptor Type ◽  
Polymorphic Ventricular Tachycardia ◽  
Atrial Arrhythmias ◽  
Initial Manifestation ◽  
Life Threatening

AbstractCatecholaminergic polymorphic ventricular tachycardia is a rare life-threatening arrhythmogenic disorder. An association with paroxysmal atrial fibrillation and other atrial arrhythmias has been described, but in all published cases the initial manifestation of the disease was ventricular arrhythmia. This is the first report about a patient who presented with complex atrial tachycardia and sinus node dysfunction about 1 year before the typical ventricular arrhythmias were observed, leading to the diagnosis of catecholaminergic polymorphic ventricular tachycardia. In this girl, a mutation of the ryanodine receptor type 2 gene, which has not been described so far, was discovered.

scholarly journals Dissociation of FKBP12.6 from ryanodine receptor type 2 is regulated by cyclic ADP-ribose but not β-adrenergic stimulation in mouse cardiomyocytes

2009 ◽  
Vol 84 (2) ◽  
pp. 253-262 ◽  
Author(s):  
Xu Zhang ◽  
Yvonne N. Tallini ◽  
Zheng Chen ◽  
Lu Gan ◽  
Bin Wei ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Receptor Type ◽  
Adrenergic Stimulation ◽  
Cyclic Adp Ribose

scholarly journals Functional study of a N-terminal CPVT mutation RyR2R420Q in patient specific hiPSC-CMs model

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
L Yin ◽  
P Joanne ◽  
R Perrier ◽  
P Gerbaud ◽  
P Lechene ◽  
...  
Keyword(s):  
Induced Pluripotent Stem Cell ◽  
Calcium Transient ◽  
Polymorphic Ventricular Tachycardia ◽  
Functional Study ◽  
Patient Specific ◽  
Control Group ◽  
Structural Abnormality ◽  
Loss Of Function ◽  
Adrenergic Stimulation ◽  
Gain Of Function

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ANR (Agence Nationale de la Rercherche) Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal genetic arrhythmia that manifests by syncope or sudden death in children and young adults under stress conditions without obvious cardiac structural abnormality. A novel CPVT mutation located in the RyR2 N terminal portion has been identified in a Spanish family (RyR2R420Q). According to the studies of RyR2 function in HEK293 cell line, this mutation presented gain of function at low cytosolic intracellular Ca2+ concentration ([Ca2+]i) and loss of function at high [Ca2+]i. Moreover, KI mice heterozygous for this mutation presented bradycardia and sino-atrial node (SAN) dysfunction. Here we generated induced pluripotent stem cell (hiPSC) from two brothers (one with mutation, the other without mutation as control) of this family and differentiated them into cardiomyocytes (hiPSC-CM). In order to verify that the differentiated cells were well cardiomyocytes, we did immunofluorescence labelling to detect the α-actinin expression and found that around 90% cells were α-actinin positive in both groups of hiPS-CMs. Then the calcium transient was studied by confocal microscopy and the action potential (AP) by micro-electrode technique. The characteristics of spontaneous AP of mutated cells were mostly similar to that of control cells, but more mutated cells presented proarrhythmic behaviors under adrenergic stimulation. hiPSC-CM are immature cardiomyocytes and contract spontaneously. In order to be able to analyze [Ca2+]i transient characteristics, we paced the cells at a constant rate of 1 Hz by field stimulation through two Pt electrodes. Sarcoplasmic reticulum (SR) Ca2+ load was estimated by rapid caffeine (10 mM) application. hiPSC-CMs from the RyR2R420Q carrier presented smaller SR Ca2+ load than those from the control person, whereas their fractional release (the [Ca2+]i transient normalized by the amount of Ca2+ stored in the SR) was higher than that in control group, indicating a gain-of-function mutation.  Even if SR Ca2+ load was smaller in RyR2R420Q cells, they often presented proarrhythmogenic behavior such as Ca2+ waves. The fact was further enhanced during β-adrenergic stimulation, pointing to this model as a valuable tool to study the CPVT disease in human cells.

scholarly journals Cardiac ryanodine receptor calcium release deficiency syndrome

2021 ◽  
Vol 13 (579) ◽  
pp. eaba7287
Author(s):  
Bo Sun ◽  
Jinjing Yao ◽  
Mingke Ni ◽  
Jinhong Wei ◽  
Xiaowei Zhong ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Ventricular Arrhythmias ◽  
Calcium Release ◽  
Deficiency Syndrome ◽  
Exercise Stress ◽  
Polymorphic Ventricular Tachycardia ◽  
Loss Of Function ◽  
Electrophysiological Studies ◽  
Genetic Evaluations ◽  
Cardiac Ryanodine Receptor

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies.

scholarly journals Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function

2015 ◽  
Vol 112 (13) ◽  
pp. E1669-E1677 ◽  
Author(s):  
Yan-Ting Zhao ◽  
Carmen R. Valdivia ◽  
Georgina B. Gurrola ◽  
Patricia P. Powers ◽  
B. Cicero Willis ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Ryanodine Receptor ◽  
Single Channel ◽  
Ventricular Myocytes ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Channel Activity ◽  
Loss Of Function ◽  
Human Patient ◽  
Essential Components

Current mechanisms of arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia (CPVT) require spontaneous Ca2+ release via cardiac ryanodine receptor (RyR2) channels affected by gain-of-function mutations. Hence, hyperactive RyR2 channels eager to release Ca2+ on their own appear as essential components of this arrhythmogenic scheme. This mechanism, therefore, appears inadequate to explain lethal arrhythmias in patients harboring RyR2 channels destabilized by loss-of-function mutations. We aimed to elucidate arrhythmia mechanisms in a RyR2-linked CPVT mutation (RyR2-A4860G) that depresses channel activity. Recombinant RyR2-A4860G protein was expressed equally as wild type (WT) RyR2, but channel activity was dramatically inhibited, as inferred by [3H]ryanodine binding and single channel recordings. Mice heterozygous for the RyR2-A4860G mutation (RyR2-A4860G+/−) exhibited basal bradycardia but no cardiac structural alterations; in contrast, no homozygotes were detected at birth, suggesting a lethal phenotype. Sympathetic stimulation elicited malignant arrhythmias in RyR2-A4860G+/− hearts, recapitulating the phenotype originally described in a human patient with the same mutation. In isoproterenol-stimulated ventricular myocytes, the RyR2-A4860G mutation decreased the peak of Ca2+ release during systole, gradually overloading the sarcoplasmic reticulum with Ca2+. The resultant Ca2+ overload then randomly caused bursts of prolonged Ca2+ release, activating electrogenic Na+-Ca2+ exchanger activity and triggering early afterdepolarizations. The RyR2-A4860G mutation reveals novel pathways by which RyR2 channels engage sarcolemmal currents to produce life-threatening arrhythmias.

GNA11 loss-of-function mutations cause familial hypocalciuric hypercalcaemia type 2 (FHH2)

2013 ◽  
pp. 1-1
Author(s):  
Fadil Hannan ◽  
M A Nesbit ◽  
Sarah Howles ◽  
Valerie Babinsky ◽  
Treena Cranston ◽  
...  
Keyword(s):  
Loss Of Function
Sign in / Sign up

Export Citation Format

Share Document