Faculty Opinions recommendation of Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype.

Some mutations of the sodium channel gene NaV1.5 are multifunctional, causing combinations of LQTS, Brugada syndrome and progressive cardiac conduction system disease (PCCD). The combination of Brugada syndrome and PCCD is uncommon, although they both result from a reduction in the sodium current. We hypothesize that slow conduction is sufficient to cause S-T segment elevation and undertook a combined experimental and theoretical study to determine whether conduction slowing alone can produce the Brugada phenotype. Deletion of lysine 1479 in one of two positively charged clusters in the III/IV inter-domain linker causes both syndromes. We have examined the functional effects of this mutation using heterologous expression of the wild-type and mutant sodium channel in HEK-293-EBNA cells. We show that ΔK1479 shifts the potential of half-activation, V1/2m, to more positive potentials ( V1/2m = −36.8 ± 0.8 and −24.5 ± 1.3 mV for the wild-type and ΔK1479 mutant respectively, n = 11, 10). The depolarizing shift increases the extent of depolarization required for activation. The potential of half-inactivation, V1/2h, is also shifted to more positive potentials ( V1/2h = −85 ± 1.1 and −79.4 ± 1.2 mV for wild-type and ΔK1479 mutant respectively), increasing the fraction of channels available for activation. These shifts are quantitatively the same as a mutation that produces PCCD only, G514C. We incorporated experimentally derived parameters into a model of the cardiac action potential and its propagation in a one dimensional cable (simulating endo-, mid-myocardial and epicardial regions). The simulations show that action potential and ECG changes consistent with Brugada syndrome may result from conduction slowing alone; marked repolarization heterogeneity is not required. The findings also suggest how Brugada syndrome and PCCD which both result from loss of sodium channel function are sometimes present alone and at other times in combination.

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Abstract 5317: Identification and Characterization of a Novel Susceptibility Gene, SCN3B, for Idiopathic Ventricular Fibrillation

Circulation ◽

10.1161/circ.118.suppl_18.s_526 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Carmen R Valdivia ◽

Argelia Mereidos-Domingo ◽

Thimothy J Algiers ◽

Michael J Ackerman ◽

Jonathan C Makielski

Keyword(s):

Ventricular Fibrillation ◽

Sodium Channel ◽

Brugada Syndrome ◽

Mutational Analysis ◽

Sodium Current ◽

Susceptibility Gene ◽

Site Directed Mutagenesis ◽

Macromolecular Complex ◽

Patch Clamp Technique ◽

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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Sodium Current and Potassium Transient Outward Current Genes in Brugada Syndrome: Screening and Bioinformatics

Canadian Journal of Cardiology ◽

10.1016/j.cjca.2011.11.011 ◽

2012 ◽

Vol 28 (2) ◽

pp. 196-200 ◽

Cited By ~ 18

Author(s):

Anders G. Holst ◽

Siamak Saber ◽

Massoud Houshmand ◽

Elena V. Zaklyazminskaya ◽

Yinman Wang ◽

...

Keyword(s):

Brugada Syndrome ◽

Sodium Current ◽

Outward Current ◽

Transient Outward Current

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A Family with Liddle’s Syndrome Caused by a New Missense Mutation in the β Subunit of the Epithelial Sodium Channel

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.6.5030 ◽

1998 ◽

Vol 83 (6) ◽

pp. 2210-2213 ◽

Cited By ~ 5

Author(s):

Junnosuke Inoue ◽

Taisuke Iwaoka ◽

Hiroshi Tokunaga ◽

Kazufumi Takamune ◽

Shojiro Naomi ◽

...

Keyword(s):

Sodium Channel ◽

Missense Mutation ◽

Sodium Current ◽

Epithelial Sodium Channel ◽

Missense Mutations ◽

Β Subunit ◽

Dominant Form ◽

Liddle’S Syndrome ◽

Liddle's Syndrome ◽

Py Motif

Liddle’s syndrome is an autosomal dominant form of salt sensitive hypertension caused by mutations in the β or γ subunit of the epithelial sodium channel. Systemic mutagenesis studies revealed that a conserved PPPXY sequence (PY motif) of the C-terminus of the α, β, or γ subunits might be involved in the regulation of the channel activity. However, only two missense mutations in the PY motif of theβ subunit have been reported to cause Liddle’s syndrome. We sequenced the C-termini of the β and γ subunits of the epithelial sodium channel in a Japanese family clinically diagnosed as having Liddle’s syndrome and found a new missense mutation in the PY motif of the β subunit, P615S. Expression studies with P615S mutant in Xenopus oocytes resulted in an about 3-fold increase in the amiloride-sensitive sodium current compared to the wild type (p = 0.001). These findings provide further clinical evidence for the hypothesis that a conserved PY motif may be critically important for the regulation of the epithelial sodium channel.

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P263Biophysical consequences of missense mutations associated with Brugada syndrome

Cardiovascular Research ◽

10.1093/cvr/cvy060.183 ◽

2018 ◽

Vol 114 (suppl_1) ◽

pp. S67-S67

Author(s):

A Zaytseva ◽

A Karpushev ◽

E Mikhailov ◽

Y Fomicheva ◽

E Vasichkina ◽

...

Keyword(s):

Brugada Syndrome ◽

Missense Mutations

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Abstract 2927: Long QT Syndrome as a Cause of Stillbirths

Circulation ◽

10.1161/circ.116.suppl_16.ii_653-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Lia Crotti ◽

Roberto Insolia ◽

Alice Ghidoni ◽

Patrizio Antonazzo ◽

Fabio Facchinetti ◽

...

Keyword(s):

Long Qt Syndrome ◽

Sodium Current ◽

Sudden Infant Death ◽

Sudden Infant ◽

Missense Mutations ◽

Long Qt ◽

Late Sodium Current ◽

Qt Syndrome ◽

Reliable Quantification ◽

Ion Channel Diseases

Background : Stillbirths (intrauterine fetal deaths occurring after the 22 th week of gestation) notably contribute to perinatal mortality. Among them, 25–50% of cases remain unexplained after thorough investigation. We recently demonstrated that 10% of Sudden Infant Death Syndrome (SIDS) cases carry functionally relevant genetic variants in Long QT Syndrome (LQTS) genes. We previously hypothesized that severe forms of LQTS could contribute to mortality not only shortly after birth but also before. Accordingly, we are now screening LQTS genes in unexplained stillbirths. Materials and Methods : We receive DNA from an ongoing Italian multicenter study on rigorously defined ``unexplained stillbirths”. DNA is extracted from placenta or umbilical cord. Through DHPLC and sequence analysis we screen the main LQTS genes: KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2. Any amino-acid substitution identified in the samples is checked in a control population of 122 Caucasian controls. Here, we report the preliminary data on the first 17 cases (gestational age of death: 23–38 weeks). Results : A total of 3 missense mutations have been identified in 3 of 17 stillbirths (18%). Two were on SCN5A and one on KCNH2 . The two mutations on SCN5A (V1951L; P2006A) have been previously associated to SIDS and shown to increase the late sodium current. The mutation on KCNH2 is a novel genetic variant absent in 244 reference alleles and never described in any control populations. We are currently performing the electrophysiological cellular studies to define its functional effect. Conclusions : The initial data from this ongoing study already indicate that a yet to be defined but potentially significant number of currently unexplained intrauterine fetal deaths might be caused by ion channel diseases such as LQTS. The completion of our study will soon provide a reliable quantification of this contribution. There are potentially important implications for the affected families, ranging from prevention of recurrences to identification of other affected family members and to possible prevention of SIDS or later sudden deaths in subsequent siblings.

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