A novel de novo calmodulin mutation in a 6-year-old boy who experienced an aborted cardiac arrest

Takahashi, Kazuhiro; Ishikawa, Taisuke; Makita, Naomasa; Takefuta, Kiyotaka; Nabeshima, Taisuke; Nakayashiro, Mami

doi:10.1016/j.hrcr.2016.09.004

Cited by 18 publications

(13 citation statements)

References 14 publications

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“…Since then, scattered reports on few patients and isolated families emerged. [2][3][4][5][6][7][8][9][10][11][12][13] The phenotype most frequently shown by patients with CALM mutations was LQTS, 1,[4][5][6][7][8]12 but some had catecholaminergic polymorphic ventricular tachycardia (CPVT) 2,10 or idiopathic ventricular fibrillation (IVF). 3 CALM mutations were also identified in autopsy-negative sudden unexplained deaths (SUD) in young individuals.…”

Section: Introductionmentioning

confidence: 99%

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry

Crotti

Spazzolini

Tester

et al. 2019

European Heart Journal

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Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

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Section: Introductionmentioning

confidence: 99%

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry

Crotti

Spazzolini

Tester

et al. 2019

European Heart Journal

Self Cite

146

181

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“…Mutations in CaM are clinically associated with long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation (Nyegaard et al, 2012;Crotti et al, 2013;Makita et al, 2014;Boczek et al, 2016;Takahashi et al, 2017). Genetic predisposition to ventricular arrhythmias is associated with mutations in CaM-regulated cardiac ion channels [ryanodine receptor, voltage-gated calcium channels (Ca V ), voltage-gated potassium channels and Na V ; Wang et al, 1995Wang et al, , 1996Priori et al, 2001;Splawski et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

NaV1.2 EFL domain allosterically enhances Ca2+ binding to sites I and II of WT and pathogenic calmodulin mutants bound to the channel CTD

et al. 2021

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Na V 1.2 EFL domain allosterically enhances Ca 2+ binding to sites I and II of WT and pathogenic calmodulin mutants bound to the channel CTD Graphical abstract Highlights d In solution, only the IQ motif of Na V 1.2 CTD(1,777-1,937) contacts CaM ± Ca 2+ d Ca 2+ changes interfaces of CaM + Na V 1.2-IQ p and CaM + Na V 1.2-CTD complexes identically d Ca 2+ binds to N-domain sites of CaM + Na V 1.2-CTD preferentially relative to free CaM d Apo pathogenic CaM mutants bind the Na V 1.2 CTD as well or better than WT CaM

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“…Over the last few years, several genetic and clinical reports have identified a number of missense mutations in all three CaM genes that encode for an identical protein, in individuals with a family history of life‐threatening arrhythmogenic cardiac disorders and early onset sudden cardiac death . A recent genetic report identified a novel de novo LQTS‐associated missense CaM mutation (E105A) in a 6‐year‐old boy with no family history of heart disease, who experienced an aborted first episode of cardiac arrest …”

Section: Discussionmentioning

confidence: 99%

“…The patient had no family history of heart disease while his parents’ ECGs appeared to be normal. Genetic screening revealed a novel de novo missense variation c.A314>C in exon 5 of CALM1 of this patient . This nucleotide change results in the substitution of a conserved glutamic acid (E) with an alanine (A) residue (p.E105A) within the third EF‐hand motif in the C‐domain of CaM protein.…”

Section: Introductionmentioning

confidence: 94%

“…A recent clinical study reported a case of aborted cardiac arrest in a seemingly healthy 6‐year‐old boy who exhibited profound QT prolongation with an increasing heart rate before the recurrence of polymorphic ventricular tachycardia at a pediatric intensive care unit . The patient had no family history of heart disease while his parents’ ECGs appeared to be normal.…”

Section: Introductionmentioning

confidence: 99%

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Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish

Da’as

Thanassoulas

Calver

et al. 2019

Annals of the New York Academy of Sciences

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Calmodulin (CaM) is a universal calcium (Ca2+)‐binding messenger that regulates many vital cellular events. In cardiac muscle, CaM associates with ryanodine receptor 2 (RyR2) and regulates excitation–contraction coupling. Mutations in human genes CALM1, CALM2, and CALM3 have been associated with life‐threatening heart disorders, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia. A novel de novo LQTS‐associated missense CaM mutation (E105A) was recently identified in a 6‐year‐old boy, who experienced an aborted first episode of cardiac arrest. Herein, we report the first molecular characterization of the CaM E105A mutation. Expression of the CaM E105A mutant in zebrafish embryos resulted in cardiac arrhythmia and increased heart rate, suggestive of ventricular tachycardia. In vitro biophysical and biochemical analysis revealed that E105A confers a deleterious effect on protein stability and a reduced Ca2+‐binding affinity due to loss of cooperativity. Finally, the CaM E105A mutation resulted in reduced CaM–RyR2 interaction and defective modulation of ryanodine binding. Our findings suggest that the CaM E105A mutation dysregulates normal cardiac function by a complex mechanism involving alterations in both CaM–Ca2+ and CaM–RyR2 interactions.

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A novel de novo calmodulin mutation in a 6-year-old boy who experienced an aborted cardiac arrest

Cited by 18 publications

References 14 publications

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry

NaV1.2 EFL domain allosterically enhances Ca2+ binding to sites I and II of WT and pathogenic calmodulin mutants bound to the channel CTD

Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish

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