scholarly journals Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation

2020 ◽  
Vol 8 ◽  
Author(s):  
Wener Li ◽  
Michael Stauske ◽  
Xiaojing Luo ◽  
Stefan Wagner ◽  
Meike Vollrath ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Loss Of Function ◽  
Disease Phenotypes ◽  
Scn5a Mutation

Abstract 1825: Abnormal ECG Markers suggest that Accentuated Intracardiac Conduction Delay is The Common and Distinguishing Feature of Patients with Spontaneous Type 1 ECG or SCN5A Mutation in Brugadas Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Juliane Theilade ◽  
Raffaella Bloise ◽  
Janny Nastoli ◽  
Elena Ronchetti ◽  
S. Facchinetti ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Relative Size ◽  
Conduction Delay ◽  
List Type ◽  
Late Potentials ◽  
Loss Of Function ◽  
Intraventricular Conduction ◽  
Qrs Duration ◽  
Scn5a Mutation

The conclusive diagnosis of Brugada Syndrome (BrS) is established in patients (pts) with spontaneous type 1 ECG or in carriers of a loss of function SCN5A mutation. We carried out a systematic analysis of ECG recordings in BrS pts to test the hypothesis that the presence of intraventricular (Intra-Ven) and atrioventricular (A-Ven) conduction delay is the distinguishing common feature of pts with SCN5A mutations (Mut+) and in pts with a spontaneous type 1 ECG pattern (spont-ECG). We assessed the following 5 ECG parameters: late potentials (quantified as RMS at 40 Hz), aVR sign (relative size of the R and q waves in aVR), QRS complex fragmentation (defined as an additional R′ or notching of the of S wave), PQ and QRS duration. We studied 200 consecutive BrS pts to define whether the prevalence of ECG markers correlate with 1) the presence of a SCN5A mutation (Mut+) or 2) the presence of a spontaneous type 1 pattern ECG (spont-ECG). Results are summarized in the table . Interestingly, Mut+ not only presented prolonged PQ (p<0.003 vs Mut÷) as previously reported but more significantly they showed the presence of abnormal markers of intraventricular conduction (QRS duration, aVR sign and late potentials). Similarly, also the presence of a spont-ECG was associated with prolonged PQ and QRS intervals and with late potentials. Based on our ECG analysis we propose that Brugada syndrome is a disease characterized by impairment of A-Ven and Intra-Ven conduction, the presence of a mutation in the SCN5A gene and, the presence of a spontaneous type 1 ECG identify patients with accentuated conduction defects. These findings suggest that the presence of interventricular conduction delay is a landmark of BrS and should be considered as diagnostic markers in BrS.

Abstract 5676: Elevated Oxidative Stress is Associated with Ventricular Fibrillation Episode in Patients with Brugada Syndrome without SCN5A Mutation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masamichi Tanaka ◽  
Keiko Ohgou ◽  
Koji Nakagawa ◽  
Takeshi Tada ◽  
Masato Murakami ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factor ◽  
Ventricular Fibrillation ◽  
Brugada Syndrome ◽  
Endomyocardial Biopsy ◽  
Heart Diseases ◽  
Multivariable Analysis ◽  
Pathophysiological Mechanism ◽  
Normal Heart ◽  
Scn5a Mutation

Background; Brugada Syndrome (BS) is a disease known to cause ventricular fibrillation (VF) with structurally normal heart. Gene mutation (i.e. SCN5A) has been proposed to be related to the development of BS and VF. However, the pathophysiological mechanism associated with VF development without SCN5A mutation has not been studied yet. Oxidative stress is a common disorder that is related to many heart diseases. We have previously demonstrated that oxidative stress is closely linked to the arrhythmic development. Accordingly, we examined 4-hydroxy-2-nonenal (HNE) modified protein, which is a common mediator of oxidative stress in the myocardium, and VF episodes in patients with BS. Methods; We collected sixty-eight BS patients that underwent right ventricular endomyocardial biopsy (66 males, 2 female; mean age 49.0±11.6 years old). VF was documented in 11 and SCN5A mutation was detected in 14 patients. Biopsy samples were processed for histology [Masson’s trichrome staining for fibrosis, immuno staining for CD45, CD68, and HNE modified protein]. All results from histology were compared with VF episodes. We also performed the analysis in VF patients with (n=14) or without SCN5A mutations (n=54). Results: HNE positive area was significantly larger in VF patients [VF(+): 16.3±10.5, VF(−): 9.3±5.7%: P=0.029]. All other parameters (fibrosis area, CD45, and CD68) were not different between the groups. In multivariable analysis, HNE positive area was most important risk factor of VF development in patients without SCN5A mutation (P=0.004). Conclusions ; These data suggested that oxidative stress is associated with VF development in BS patients, especially in patients without SCN5A mutation.

Abstract 14356: Blood Tests That Improve the Accuracy of a Brugada Syndrome Diagnosis

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Anyu Zhou ◽  
Ning Jinag ◽  
Marco Denegri ◽  
An Xie ◽  
Guangbin Shi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Brugada Syndrome ◽  
Roc Analysis ◽  
White Blood Cells ◽  
Control Group ◽  
Mrna Levels ◽  
Operating Characteristics ◽  
Optimal Cutoff ◽  
Scn5a Mutation

Objectives: To discover the role of altered gene expression regulation in Brugada Syndrome (BrS) and to find biomarkers for BrS diagnosis. Methods: Twenty-five control patients (Control), 25 BrS patients without SCN5A mutation (SCN5A(-)) and 20 BrS patients with SCN5A mutation (SCN5A(+)) were included in this study. Specified gene expression of white blood cells (WBC) were measured by RT-qPCR using TaqMan® Gene Expression assay. Results: MEF2C and MESP1 are the two major cardiac specific transcription factors expressed in WBC. The mRNA expression levels of SCN5A, MEF2C and HuR, one of mRNA stabilizers, were decreased in the SCN5A (+) group (P=0.047, 0.02, 0.000 vs. control group, respectively). The mRNA expression of MESP1 in WBCs was significantly lower in both SCN5A(-) (P=0.012 vs. control) and SCN5A(+) (P=0.000 vs. control) groups. There was no difference between the two BrS groups in MESP1 expression (P=0.215). The area under the Receiver Operating Characteristics (ROC) analysis curve for prediction of BrS using MESP1 levels was 0.775 (95% CI 0.668, 0.882, asymptotic Sig.=0.000). At the optimal cutoff, the corresponding maximum sensitivity and specificity were 0.62 (95% CI: 0.47, 0.76) and 0.88 (0.69, 0.97), respectively. The diagnostic odds ratio (DOR) of MESP1 for BrS diagnosis was 11.96 (95% CI: 5.79, 24.73). The assessment of the mRNA levels in blood SCN5A, MEF2C and HuR were useful for predicting BrS patients with an SCN5A mutation. The area under the ROC analysis curve for prediction of BrS with an SCN5A mutation using SCN5A, MEF2C and HuR mRNA levels in WBCs was 0.847 (95% CI 0.752, 0.942, asymptotic Sig.=0.000), 0.685 (95% CI 0.542, 0.828, asymptotic Sig.=0.016) and 0.777 (95% CI 0.652, 0.902, asymptotic Sig.=0.000), respectively. At the optimal cutoff, the DOR of SCN5A, MEF2C and HuR for SCN5A(+) BrS diagnosis was 17.5 (95% CI: 8.06, 37.86), 4.9 (95% CI: 2.61, 9.17) and 23.5 (95% CI: 9.39, 58.80), respectively. Conclusions: Our results suggest that assessment of circulating MESP1 may be used as a biomarker for BrS diagnosis while decreased SCN5A, MEF2C and HuR mRNA in WBCs is associated with BrS patients with an SCN5A mutation. Our results also suggest that decreased expression of SCN5A, MEF2C, MESP1, and HuR may be pathophysiologically related to BrS.

Abstract 808: Functional Characterization of a Novel Scn5a Mutation Associated With the Brugada Syndrome

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Anthony Frosio ◽  
David Molla ◽  
Giorgia Bertoli ◽  
Claudia Bazzini ◽  
Raffaella Milanesi ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Functional Characterization ◽  
Scn5a Mutation

scholarly journals Essential Roles in Development and Pigmentation for the Drosophila Copper Transporter DmATP7

2006 ◽  
Vol 17 (1) ◽  
pp. 475-484 ◽  
Author(s):  
Melanie Norgate ◽  
Esther Lee ◽  
Adam Southon ◽  
Ashley Farlow ◽  
Philip Batterham ◽  
...  
Keyword(s):  
Copper Homeostasis ◽  
Cellular Level ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Copper Transporter ◽  
Disease Phenotypes ◽  
In Vivo Analysis ◽  
Cellular Copper ◽  
P Type

Defects in the mammalian Menkes and Wilson copper transporting P-type ATPases cause severe copper homeostasis disease phenotypes in humans. Here, we find that DmATP7, the sole Drosophila orthologue of the Menkes and Wilson genes, is vital for uptake of copper in vivo. Analysis of a DmATP7 loss-of-function allele shows that DmATP7 is essential in embryogenesis, early larval development, and adult pigmentation and is probably required for copper uptake from the diet. These phenotypes are analogous to those caused by mutation in the mouse and human Menkes genes, suggesting that like Menkes, DmATP7 plays at least two roles at the cellular level: delivering copper to cuproenzymes required for pigmentation and neuronal function and removing excess cellular copper via facilitated efflux. DmATP7 displays a dynamic and unexpected expression pattern in the developing embryo, implying novel functions for this copper pump and the lethality observed in DmATP7 mutant flies is the earliest seen for any copper homeostasis gene.

scholarly journals Comparative Study of the Effects of an SCN5A Mutation within a Family Diagnosed with Brugada Syndrome using iPS-CM

2020 ◽  
Vol 118 (3) ◽  
pp. 500a
Author(s):  
Rebecca Martinez-Moreno ◽  
David Carreras ◽  
Elisabet Selga ◽  
Georgia Sarquella-Brugada ◽  
Ramon Brugada ◽  
...  
Keyword(s):  
Comparative Study ◽  
Brugada Syndrome ◽  
Scn5a Mutation
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