A sodium channel pore mutation causing Brugada syndrome

Pfahnl, Arnold; Viswanathan, Prakash C.; Weiss, Raul; Shang, Lijuan L.; Sanyal, Shamarendra; Shusterman, Vladimir; Kornblit, Cari A.; London, Barry; Dudley, Samuel C.

doi:10.1016/j.hrthm.2006.09.031

Cited by 60 publications

(44 citation statements)

References 53 publications

(16 reference statements)

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“…Several mutations in SCN5A that affect trafficking already have been described as causing a BrS phenotype. 16,[22][23][24][25] Indeed, a reduced channel density at the membrane has been observed for the GDP1L mutation associated with a BrS family 18 as well as for an SCN3B mutation in 1 individual with BrS. 20 Therefore, in accordance with these previous studies, the E83D-MOG1 mutation may cause BrS by reducing Na v 1.5 channel trafficking to the cell surface.…”

Section: Kattygnarath Et Al Dominant Negative Mog1 Brugada Syndrome Msupporting

confidence: 80%

MOG1

Kattygnarath

Maugenre

Neyroud

et al. 2011

Circ Cardiovasc Genet

150

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Background-Brugada syndrome (BrS) is caused mainly by mutations in the SCN5A gene, which encodes the ␣-subunit of the cardiac sodium channel Na v 1.5. However, Ϸ20% of probands have SCN5A mutations, suggesting the implication of other genes. MOG1 recently was described as a new partner of Na v 1.5, playing a potential role in the regulation of its expression and trafficking. We investigated whether mutations in MOG1 could cause BrS. Methods and Results-MOG1 was screened by direct sequencing in patients with BrS and idiopathic ventricular fibrillation.A missense mutation p.Glu83Asp (E83D) was detected in a symptomatic female patient with a type-1 BrS ECG but not in 281 controls. Wild type (WT)-and mutant E83D-MOG1 were expressed in HEK Na v 1.5 stable cells and studied using patch-clamp assays. Overexpression of WT-MOG1 alone doubled sodium current (I Na ) density compared to control conditions (PϽ0.01). In contrast, overexpression of mutant E83D alone or E83DϩWT failed to increase I Na (PϽ0.05), demonstrating the dominant-negative effect of the mutant. Microscopy revealed that Na v 1.5 channels failed to properly traffic to the cell membrane in the presence of the mutant. Silencing endogenous MOG1 demonstrated a 54% decrease in I Na density. Conclusions-Our results support the hypothesis that dominant-negative mutations in MOG1 can impair the trafficking of Na v 1.5 to the membrane, leading to I Na reduction and clinical manifestation of BrS. Moreover, silencing MOG1 reduced I Na , demonstrating that MOG1 is likely to be important in the surface expression of Na v 1.5 channels. All together, our data support MOG1 as a new susceptibility gene for BrS. (Circ Cardiovasc Genet. 2011;4:261-268.)

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Section: Kattygnarath Et Al Dominant Negative Mog1 Brugada Syndrome Msupporting

confidence: 80%

MOG1

Kattygnarath

Maugenre

Neyroud

et al. 2011

Circ Cardiovasc Genet

150

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“…The Brugada syndrome SCN5A mutations, T351I, R367H, R1232W, R1232W/T1620M, R1432G, and G1743R are trafficking deficient to have small I Na . 79–81 Culture with antiarrhythmic drugs (flecainide, mexiletine, or quinidine) increased I Na for most but not all mutations, the efficiency of pharmacological rescue varied with the mutation and with the drug, and I Na was increased even for WT SCN5A channels. The R282H SCN5A Brugada syndrome mutation, when coexpressed with the H558R SCN5A polymorphism, rescues the defective I Na , 82 suggesting that the allele products interact to facilitate expression of the mutant channels, and this may be a mechanism for variable penetrance.…”

Section: Cardiac Cellular Electrophysiologymentioning

confidence: 99%

Rescue of Mutated Cardiac Ion Channels in Inherited Arrhythmia Syndromes

Balijepalli

Anderson

Lin

et al. 2010

Journal of Cardiovascular Pharmacology

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Inherited arrhythmia syndromes comprise an increasingly complex group of diseases involving mutations in multiple genes encoding ion channels, ion channel accessory subunits and channel interacting proteins, and various regulatory elements. These mutations serve to disrupt normal electrophysiology in the heart, leading to increased arrhythmogenic risk and death. These diseases have added impact as they often affect young people, sometimes without warning. Although originally thought to alter ion channel function, it is now increasingly recognized that mutations may alter ion channel protein and messenger RNA processing, to reduce the number of channels reaching the surface membrane. For many of these mutations, it is also known that several interventions may restore protein processing of mutant channels to increase their surface membrane expression toward normal. In this article, we reviewed inherited arrhythmia syndromes, focusing on long QT syndrome type 2, and discuss the complex biology of ion channel trafficking and pharmacological rescue of disease-causing mutant channels. Pharmacological rescue of misprocessed mutant channel proteins, or their transcripts providing appropriate small molecule drugs can be developed, has the potential for novel clinical therapies in some patients with inherited arrhythmia syndromes.

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“…12 The truncated SCN5A cDNAs labeled either with internal ribosome entry site (IRES)-mediated green fluorescent protein (GFP) or GFP fused to the channel C terminus were transfected into human embryonic kidney (HEK) cells or a HEK cell line stably expressing the full-length human SCN5A cDNA (HEK-SCN5A). HEK cell lines stably expressing the truncation variants were created by selection for 3 weeks with geneticin after transfection.…”

Section: Scn5a Cdnamentioning

confidence: 99%

Human Heart Failure Is Associated With Abnormal C-Terminal Splicing Variants in the Cardiac Sodium Channel

Shang

Pfahnl

Sanyal

et al. 2007

Circulation Research

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117

112

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Abstract-Heart failure (HF) is associated with reduced cardiac Na ϩ channel (SCN5A) current. We hypothesized that abnormal transcriptional regulation of this ion channel during HF could help explain the reduced current. Using human hearts explanted at the transplantation, we have identified 3 human C-terminal SCN5A mRNA splicing variants predicted to result in truncated, nonfunctional channels. As compared with normal hearts, the explanted ventricles showed an upregulation of 2 of the variants and a downregulation of the full-length mRNA transcript such that the E28A transcript represented only 48.5% (PϽ0.01) of the total SCN5A mRNA. This correlated with a 62.8% (PϽ0.01) reduction in Na ϩ channel protein. Lymphoblasts and skeletal muscle expressing SCN5A also showed identical C-terminal splicing variants. Variants showed reduced membrane protein and no functional current. Transfection of truncation variants into a cell line stably transfected with the full-length Na ϩ channel resulted in dose-dependent reductions in channel mRNA and current. Introduction of a premature truncation in the C-terminal region in a single allele of the mouse SCN5A resulted in embryonic lethality. Embryonic stem cell-derived cardiomyocytes expressing the construct showed reductions in Na ϩ channel-dependent electrophysiological parameters, suggesting that the presence of truncated Na ϩ channel mRNA at levels seen in HF is likely to be physiologically significant. In summary, chronic HF was associated with an increase in 2 truncated SCN5A variants and a decrease in the native mRNA. These splice variations may help explain a loss of Na Key Words: sodium channels Ⅲ transcriptional regulation Ⅲ mRNA splice variations Ⅲ heart failure Ⅲ arrhythmia H uman heart failure (HF) is associated with decreased cardiac voltage-gated sodium channel current. 1,2 Genetically mediated decreases in Na ϩ current have been implicated in the risk for sudden death, [3][4][5] and Na ϩ channel changes may contribute to the increased risk of sudden death in HF. 6,7 Because transcriptional alterations in other ion channels have been noted to contribute to current changes in HF, 8,9 we investigated Na ϩ channel protein and mRNA abundance in hearts explanted during cardiac transplantation to determine whether there were changes that might explain the reduced Na ϩ current previously reported in this tissue. Materials and Methods Detection of Human SCN5A 3UTR Variants by Rapid Amplification of cDNA Ends PCRTotal human RNA from normal fetal and adult whole hearts was purchased from Clontech (Mountain View, Calif). The RNA ligasemediated rapid amplification of cDNA ends (RACE) method was used to characterize the 3Ј ends of the human SCN5A mRNA using the GeneRacer kit (Invitrogen, Carlsbad, Calif). Primary and nested PCR reactions were performed with primers HE26F (on exon 26) and HE27F (on exon 27) specific to the human SCN5A gene and the GeneRacer 3Ј primer for amplifying the 3Ј-end fragment. The nested PCR products were cloned into pCR4-TOPO vector (Invitrogen) and se...

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A sodium channel pore mutation causing Brugada syndrome

Cited by 60 publications

References 53 publications

MOG1

MOG1

Rescue of Mutated Cardiac Ion Channels in Inherited Arrhythmia Syndromes

Human Heart Failure Is Associated With Abnormal C-Terminal Splicing Variants in the Cardiac Sodium Channel

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