Loss-of-function mutation of the SCN3B-encoded sodium channel  3 subunit associated with a case of idiopathic ventricular fibrillation

Background: Mutations in the Na V 1.5 sodium channel macromolecular complex have been identified in some cases classified as idiopathic ventricular fibrillation (IVF). IVF and Brugada syndrome (BrS) are partially overlapping syndromes. Here, we report a mutation in SCN3B- encoded sodium channel β3 subunit as a novel pathogenic mechanism for IVF. Methods: Comprehensive open reading frame mutational analysis of SCN5A, GPD1L, and the beta subunit genes ( SCN1–4B ) was performed using PCR, DHPLC, and direct DNA sequencing of DNA extracted from a 20-year-old patient diagnosed with IVF. The SCN3B mutation was made by site directed mutagenesis and co-transfected with SCN5A into HEK-293 cells for functional chraracterization using the patch clamp technique. Results: A novel missense mutation, V54G-SCN3B, was identified in a 20-year-old male following collapse and external defibrillation from VF. After recovery, there was no detectable electrocardiographic abnormality. Imaging studies demonstrated a structurally normal heart, and the patient was diagnosed with IVF. The mutation was absent in 800 reference alleles and involved a highly conserved residue in the extracellular domain of the beta 3 subunit. No other mutations were identified in the 5 other genes. HEK cells expressing SCN5A and either WT-, or V54G-SCN3B were studied 24 hours after transfection. Cells expressing V54G-SCN3B showed significant decrease in sodium current density of 60±20 pA/pF compared to 203±35 pA/pF in WT-SCN3B (n=14–19). In addition V54G-SCN3B significantly shifted the activation curve +5 mV without affecting inactivation. Conclusions: This study provides the first molecular and cellular evidence implicating SCN3B in IVF. Given the marked loss-of-function to the sodium channel by V54G-SCN3B and the overlap between IVF and BrS, it will be interesting to determine whether mutations in SCN3B explain some cases of genotype negative Brugada syndrome.

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Idiopathic ventricular fibrillation associated with early repolarization which was unmasked by a sodium channel blocker after catheter ablation of atrial fibrillation

Journal of Interventional Cardiac Electrophysiology ◽

10.1007/s10840-014-9933-8 ◽

2014 ◽

Vol 41 (2) ◽

pp. 145-146 ◽

Cited By ~ 4

Author(s):

Atsuhiko Yagishita ◽

Yasuteru Yamauchi ◽

Tohru Obayashi ◽

Kenzo Hirao

Keyword(s):

Atrial Fibrillation ◽

Catheter Ablation ◽

Ventricular Fibrillation ◽

Sodium Channel ◽

Channel Blocker ◽

Sodium Channel Blocker ◽

Early Repolarization ◽

Idiopathic Ventricular Fibrillation

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Identification of Loss-of-function RyR2 Mutations Associated with Idiopathic Ventricular Fibrillation and Sudden Death

Bioscience Reports ◽

10.1042/bsr20210209 ◽

2021 ◽

Author(s):

Xiaowei Zhong ◽

Wenting Guo ◽

Jinhong Wei ◽

Yijun Tang ◽

Yingjie Liu ◽

...

Keyword(s):

Ventricular Fibrillation ◽

Sudden Death ◽

Negative Impact ◽

Deficiency Syndrome ◽

Dominant Negative ◽

Exercise Stress ◽

Hek293 Cells ◽

Polymorphic Ventricular Tachycardia ◽

Loss Of Function ◽

Idiopathic Ventricular Fibrillation

Mutations in cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most CPVT RyR2 mutations characterized are gain-of-function (GOF), indicating enhanced RyR2 function as a major cause of CPVT. Loss-of-function (LOF) RyR2 mutations have also been identified and are linked to a distinct entity of cardiac arrhythmia termed RyR2 Ca2+ release deficiency syndrome (CRDS). Exercise stress testing (EST) is routinely used to diagnose CPVT, but it is ineffective for CRDS. There is currently no effective diagnostic tool for CRDS in humans. An alternative strategy to assess the risk for CRDS is to directly determine the functional impact of the associated RyR2 mutations. To this end, we have functionally screened 18 RyR2 mutations that are associated with idiopathic ventricular fibrillation (IVF) or sudden death. We found two additional RyR2 LOF mutations E4146K and G4935R. The E4146K mutation markedly suppressed caffeine activation of RyR2 and abolished store overload induced Ca2+ release in HEK293 cells. E4146K also severely reduced cytosolic Ca2+ activation and abolished luminal Ca2+ activation of single RyR2 channels. The G4935R mutation completely abolished caffeine activation of and [3H]ryanodine binding to RyR2. Co-expression studies showed that the G4935R mutation exerted dominant negative impact on the RyR2 wildtype channel. Interestingly, the RyR2-G4935R mutant carrier had a negative EST, and the E4146K carrier had a family history of sudden death during sleep, which are different from phenotypes of typical CPVT. Thus, our data further support the link between RyR2 LOF and a new entity of cardiac arrhythmias distinct from CPVT.

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Familial Evaluation in Idiopathic Ventricular Fibrillation

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.120.009089 ◽

2021 ◽

Vol 14 (3) ◽

Author(s):

Greg J. Mellor ◽

Lennart J. Blom ◽

Sanne A. Groeneveld ◽

Bo G. Winkel ◽

Bode Ensam ◽

...

Keyword(s):

Ventricular Fibrillation ◽

Sodium Channel ◽

Channel Blocker ◽

Risk Haplotype ◽

Sodium Channel Blocker ◽

Early Repolarization ◽

Minimum Requirement ◽

Idiopathic Ventricular Fibrillation ◽

Family Screening ◽

First Degree Relatives

Background: Familial cascade screening is well established in patients with heritable cardiac disease and in cases of sudden arrhythmic death syndrome. The clinical benefit of family screening in idiopathic ventricular fibrillation (IVF) is unknown. Methods: Patients with IVF were identified from national and institutional registries. All underwent systematic and comprehensive clinical evaluation to exclude identifiable causes of cardiac arrest with a minimum requirement of ECG, cardiac (echocardiogram or magnetic resonance imaging) and coronary imaging, exercise ECG, and sodium channel blocker provocation. Additional investigations including genetic testing were performed at the physician’s discretion. First-degree relatives who were assessed with at least a 12-lead ECG were included in the final cohort. Results of additional investigations, performed at the physician’s discretion, were also recorded. Results were coded as normal, abnormal, or minor findings. Results: We identified 201 first-degree relatives of 96 IVF patients. In addition to a 12-lead ECG, echocardiography was performed in 159 (79%) and ≥1 additional investigation in 162 (80%) relatives. An inherited arrhythmia syndrome was diagnosed in 5 (3%) individuals from 4 (4%) families. Two relatives hosted the DPP6 risk haplotype identified in a single proband, one of whom received a primary prevention implantable cardioverter defibrillator. In 3 separate families, an asymptomatic parent of the IVF proband developed a type 1 Brugada ECG pattern during sodium channel blocker provocation. All were managed with lifestyle measures only. The early repolarization (ER) ECG pattern was present in 16% probands and was more common in relatives in those families than those where the proband did not have early repolarization (25% versus 8%, P =0.04). Conclusions: The yield of family screening in relatives of IVF probands is low when the proband is comprehensively investigated. The significance of J wave syndromes in relatives and the role for systematic sodium channel blocker provocation are, however, uncertain and require further research.

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