Arrhythmogenic Calmodulin Mutations Disrupt Intracellular Cardiomyocyte Ca
            <sup>2+</sup>
            Regulation by Distinct Mechanisms

Guo, Yin; Hassan, Faisal; Haroun, Ayman; Murphy, Lisa L. Salazar; Crotti, Lia; Schwartz, Peter J.; George, Alfred L.; Satin, Jonathan

doi:10.1161/jaha.114.000996

Cited by 80 publications

(115 citation statements)

References 39 publications

(80 reference statements)

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“…It was concluded that none of the mutants interfered directly with sodium channel function. 44 The changes observed were consistent with D130G, D96V…”

Section: Accepted Manuscriptsupporting

confidence: 82%

Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease

Vassilakopoulou

Calver

Thanassoulas

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…It was concluded that none of the mutants interfered directly with sodium channel function. 44 The changes observed were consistent with D130G, D96V…”

Section: Accepted Manuscriptsupporting

confidence: 82%

Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease

Vassilakopoulou

Calver

Thanassoulas

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…7, 8, 10, 11 Here, we describe the spectrum, prevalence, and functional consequence of novel CaM variants identified within our cohort of 39 unrelated patients with genetically elusive LQTS.…”

Section: Introductionmentioning

confidence: 99%

Spectrum and Prevalence of CALM1 -, CALM2 -, and CALM3 -Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome–Associated Calmodulin Missense Variant, E141G

Boczek¹,

Gómez-Hurtado²,

Ye³

et al. 2016

Circ Cardiovasc Genet

107

120

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Background Calmodulin (CaM) is encoded by three genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca2+ and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All of these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants. Methods and Results Thirty-nine genetically elusive LQTS cases underwent whole exome sequencing to identify CaM variants. Non-synonymous CaM variants were overrepresented significantly in this heretofore LQTS cohort (15.4%) compared to exome aggregation consortium (0.04%; p<0.0001). When the clinical sequelae of these 6 CaM-positive cases was compared to the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 8 months, an average QTc of 679 ms, and a high prevalence of cardiac arrest. Functional characterization of one novel variant, E141G-CaM, revealed an 11-fold reduction in Ca2+ binding affinity and a functionally-dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release. Conclusions Overall, 15% of our genetically elusive LQTS cohort harbored non-synonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history.

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“…18 Furthermore, LQTScausing calmodulin mutations disrupt calcium-dependent inactivation of the LTCC. 25,26 Therefore, it is biologically plausible that a decrease in I Ca,L inactivation, caused by loss of triadin, could lead to prolonged cardiac action potential and an LQTS phenotype.…”

Section: +mentioning

confidence: 99%

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

et al. 2015

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Background-Long-QT syndrome (LQTS) may result in syncope, seizures, or sudden cardiac arrest. Although 16 LQTSsusceptibility genes have been discovered, 20% to 25% of LQTS remains genetically elusive. Methods and Results-We performed whole-exome sequencing child-parent trio analysis followed by recessive and sporadic inheritance modeling and disease-network candidate analysis gene ranking to identify a novel underlying genetic mechanism for LQTS. Subsequent mutational analysis of the candidate gene was performed with polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing on a cohort of 33 additional unrelated patients with genetically elusive LQTS. After whole-exome sequencing and variant filtration, a homozygous p.D18fs*13 TRDN-encoded triadin frameshift mutation was discovered in a 10-year-old female patient with LQTS with a QTc of 500 milliseconds who experienced recurrent exertion-induced syncope/cardiac arrest beginning at 1 year of age. Subsequent mutational analysis of TRDN revealed either homozygous or compound heterozygous frameshift mutations in 4 of 33 unrelated cases of LQTS (12%). All 5 TRDN-null patients displayed extensive T-wave inversions in precordial leads V 1 through V 4 , with either persistent or transient QT prolongation and severe disease expression of exercise-induced cardiac arrest in early childhood (≤3 years of age) and required aggressive therapy. The overall yield of TRDN mutations was significantly greater in patients ≤10 years of age (5 of 10, 50%) compared with older patients (0 of 24, 0%; P=0.0009). encode for critical ion channel α-subunits responsible for the cardiac action potential. However, ≈20% of patients with clinically definite LQTS remain genetically elusive. Conclusions-We identified

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Arrhythmogenic Calmodulin Mutations Disrupt Intracellular Cardiomyocyte Ca ²⁺ Regulation by Distinct Mechanisms

Cited by 80 publications

References 39 publications

Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease

Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease

Spectrum and Prevalence of CALM1 -, CALM2 -, and CALM3 -Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome–Associated Calmodulin Missense Variant, E141G

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

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Arrhythmogenic Calmodulin Mutations Disrupt Intracellular Cardiomyocyte Ca 2+ Regulation by Distinct Mechanisms

Cited by 80 publications

References 39 publications

Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease

Distinctive malfunctions of calmodulin mutations associated with heart RyR2-mediated arrhythmic disease

Spectrum and Prevalence of CALM1 -, CALM2 -, and CALM3 -Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome–Associated Calmodulin Missense Variant, E141G

Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

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Arrhythmogenic Calmodulin Mutations Disrupt Intracellular Cardiomyocyte Ca ²⁺ Regulation by Distinct Mechanisms