The regulation of TGF-β1 in cardiac death caused by variation of SCN5A gene / 中国法医学杂志

The mechanism of sudden cardiac death caused by variation in SCN5A is still unclear. Recently, the converging evidences suggest that the dysfunction of regulation mediated by transforming growth factor-β1 in cardiac fibration and reconstruction of cardiac iron channel could be main reason of SUNDS caused by variation of SCN5A. The resent progress of the mechanism of transforming growth factor-β1 in sudden cardiac death caused by variation of SCN5A gene is reviewed in this paper, hoping to provide reference for the research and practice of sudden cardiac death in forensic medicine.

The reverse effects of allitridum on sodium current decrease caused by SCN5A-F1473S mutation / 药学学报

This study was designed to test the allitridum (All) activity in correction of sodium current decrease caused by SCN5A-F1473S mutation in HEK293 cells. The result may provide a theoretical basis for screening of new drugs in the treatment of Brugada syndrome. We transferred SCN5A-F1473S channel plasmids into HEK293 cells in a transient transfection. All was administrated acutely and chronically using extracellular irrigation flow and co-culture model. The concentration of All was 30 μmol·L-1. We used whole cell patch clamp technique in voltage clamp mode to record current and gating kinetics. In order to explore the rescue function of All on decreased sodium peak current, we used confocal microscopy and Western blot to detect the expression of channel proteins in the cell membrane. We found a significant increase in sodium peak current of the 30 μmol·L-1 All HEK293 cells (269.8±16.6 pA/pF, PPV1/2,inact returns to -79.5±2.4 mV, PPPSCN5A-F1473S mutation cells. We consider that the main mechanism may be related to the reduced channel inactivation by the drug with an improvement of the migration barrier of the mutational channel.

Genetic Variation of SCN5A in Korean Patients with Sick Sinus Syndrome

BACKGROUND AND OBJECTIVES: Due to recent studies that have shown an association between the genetic variation of SCN5A and sick sinus syndrome (SSS), we sought to determine if a similar correlation existed in Korean patients with SSS. SUBJECTS AND METHODS: We enrolled 30 patients with SSS who showed a sinus pause (longer than 3.0 s) in Holter monitoring, in addition to 80 controls. All exons including the putative splicing sites of the SCN5A gene were amplified by polymerase chain reaction and sequenced either directly or following subcloning. Wild-type and single nucleotide polymorphisms were expressed in human embryonic kidney cells, and the peak sodium current (I(Na)) was analyzed using the whole-cell patch-clamp technique. RESULTS: A total of 9 genetic variations were identified: 7 variations (G87A-A29A, IVS9-3C>A, A1673G-H558R, G3823A-D1275N, T5457C-D1819D, T5963G-L1988R, and C5129T-S1710L) had been previously reported, and 2 variants (A3075T-E1025D and T4847A-F1616Y) were novel; the potential structural effects of F1616Y were analyzed in a three-dimensional model of the SCN5A domain. Patch-clamp studies at room temperature demonstrated that the peak I(Na) was significantly increased by 140% in HEK cells transfected with F1616Y compared with wild-type (-335.13 pA/pF+/-24.04, n=8 vs. -139.95 pA/pF+/-23.76, n=7, respectively). Furthermore, the voltage dependency of the activation and steady-state inactivation of F1616Y were leftward-shifted compared with wild-type (V(h) activation=-55.36 mv+/-0.22, n=8 vs. V(h) activation=-44.21 mV+/-0.17, n=7; respectively; V(h) inactivation=-104.47 mV+/-0.21, n=7 vs. V(h) inactivation=-84.89 mV+/-0.09, n=12, respectively). CONCLUSION: F1616Y may be associated with SSS.

Bases genéticas y moleculares del síndrome de Brugada mediado por canales de sodio / Genetic and molecular basis for sodium channel-mediated Brugada syndrome

El síndrome de Brugada es una enfermedad hereditaria caracterizada por una anormalidad electrocardiográfica y un aumento del riesgo de muerte súbita cardiaca. El síndrome de Brugada puede ser causado por la presencia de mutaciones en el gen SCN5A en aproximadamente el 20% de los casos familiares. El gen SCN5A codifica la subunidad a del canal iónico de sodio en las células cardiacas. Estudios realizados durante la última década en genética molecular han permitido identificar 11 nuevos genes con susceptibilidad para síndrome de Brugada además del SCN5A, lo que lleva a pensar que es una enfermedad con heterogeneidad genética y compleja de identificar en la clínica y a nivel molecular en el laboratorio. Una manera de heredar el síndrome de Brugada es por medio de un patrón de transmisión hereditaria autosómica dominante. Esta breve revisión se enfoca a describir el proceso de diagnóstico de marcadores genéticos en un caso reportado de síndrome de Brugada guiando al lector a través del proceso de identificación de las variantes genéticas responsables del síndrome y a determinar la consecuencia funcional de las mutaciones del canal de sodio sobre la alteración electrocardiográfica.

Brugada syndrome is a genetic disease that is characterized by abnormal electrocardiogram findings and an increased risk of sudden cardiac death. This syndrome is linked to mutations in the SCN5A gene in approximately 20% of Brugada syndrome probands. SCN5A encodes the a subunit of the cardiac sodium channel. Studies conducted over the past decade have identified 11 other Brugada syndrome susceptibility genes besides to SCN5A, pointing to genetic heterogeneity of the syndrome. Transmission of the disease shows an autosomal dominant inheritance pattern. This brief review focuses on a reported case of sodium channel-mediated Brugada syndrome, guiding the reader through the process of identification of the genetic variants responsible for the clinically-diagnosed syndrome, mutagenesis to clone SCN5A with and without the 2 variants identified and transfection of the 2 variants into TSA201 cells to determine the functional consequence of these genetic variants on sodium channel expression and function.

A Case of Long QT Syndrome Type 3 Aggravated by Beta-Blockers and Alleviated by Mexiletine: The Role of Epinephrine Provocation Test

Long QT syndrome (LQTs) is an uncommon genetic disease causing sudden cardiac death with Torsade de Pointes (TdP). The first line drug treatment has been known to be beta-blocker. We encountered a 15-year-old female student with LQTs who had prolonged QTc and multiple episodes of syncope or agonal respiration during sleep. Although her T wave morphology in surface electrocardiography resembled LQTs type 1, her clinical presentation was unusual. During the epinephrine test, TdP was aggravated during beta-blocker medication, but alleviated by sodium channel blocker (mexiletine). Therefore, she underwent implantable cardioverter defibrillator implantation.

The Relationship Between Gastric Myoelectric Activity and SCN5A Mutation Suggesting Sodium Channelopathy in Patients With Brugada Syndrome and Functional Dyspepsia: A Pilot Study

BACKGROUND/AIMS: SCN5A encodes the cardiac-specific NaV1.5 sodium channel, and Brugada syndrome is a cardiac conduction disorder associated with sodium channel alpha-subunit (SCN5A) mutation. The SCN5A-encoded NaV1.5 channel is also found on gastrointestinal smooth muscle and interstitial cells of Cajal. We investigated the relationship between functional dyspepsia (FD) and SCN5A mutation to evaluate sodium channelopathy in FD. METHODS: Patients with Brugada syndrome or FD were examined using upper endoscopy, electrogastrography (EGG), FD symptom questionnaire based on Rome III criteria and genetic testing for SCN5A mutation. Symptom scores of FD and EGG findings were analyzed according to SCN5A mutation. RESULTS: A total of 17 patients (4 Brugada syndrome and 13 FD) participated in the study. An SCN5A mutation was noted in 75.0% of the patients with Brugada syndrome and in 1 (7.7%) of the patients with FD. Of 4 patients with SCN5A mutation, 2 (50%) had FD. Postprandial tachygastria and bradygastria were noted in 2 (50%) and 1 (25%) of the patients with SCN5A mutation, respectively. The EGG findings were not significantly different between positive and negative mutation in 17 patients. CONCLUSIONS: Although we did not find statistically significant results, we suggest that it is meaningful to attempt to identify differences in symptoms and gastric myoelectric activity according to the presence of an SCN5A mutation by EGG analysis. The relationship between FD and sodium channelopathy should be elucidated in the future by a large-scale study.

Correlation between single nucleotide polymorphism H558R in SCN5A gene and chronic Keshan Disease complicated with hypertension, and their electrocardiogram characteristics / 中国地方病学杂志

Objectives To investigate the relationship between single nucleotide polymorphism (SNP)H558R in SCN5A gene and chronic Keshan disease (KSD) complicated with hypertension,and the relationship between H558R and occurrence of arrythmia in chronic KSD complicated with hypertension.MethodsThirty nine patients with chronic KSD complicated with hypertension and 63 geographical region matched hypertension control subjects were recruited in our study in Fuyu county,Qiqihaer city,Heilongjiang province between 2006 and 2010.H558R polymorphism in case and control groups was genotyped using the polymerase chain reaction single-strand conformation polymorphism(PCR-SSCP) and sequenced,and electrocardiography(ECG) characteristics were examined in the two groups.Case-control study analytical methods were applied to analyze the relationship between H558R and chronic KSD complicated with hypertension,and the relationship between H558R and occurrence of arrythmia in chronic KSD patients complicated with hypertension.Results Subjects of genotype 558 TC in the case group had a decreased risk of chronic KSD complicated with hypertension with odds ratio of 0.288[95％ confidence interval (CI):0.104 - 0.794],and subjects of genotype TC in chronic KSD complicated hypertension patients had a decreased risk of QRS prolongation with odds ratio of 0.061 (95％CI:0.006 - 0.612).Conclusions Polymorphism H558R in SCN5A gene may be a predisposition factor of chronic KSD complicated with hypertension and occurrence of arrythmia in chronic KSD complicated with hypertension.

Pathogenesis of Sudden Manhood Death Syndrome / 대한법의학회지

Sudden manhood death syndrome (SMDS) is a disorder found in southeast Asia, particularly Thailand, Philippines and Japan, which causes sudden cardiac death during sleep. In Korea, SMDS cases have been occasionally encountered in forensic autopsy practice. However, the incidence and pathogenesis has been rarely studied. This study to review chronologically the proposed pathogenesis of SMDS; pathology of cardiac conduction system, sleeping and breathing disorder, K+ and thiamine deficiency, mental stress, testosterone, hyperlipidemia, and narrow circumference of coronary artery. Brugada syndrome and SMDS are phenotypically, genetically and functionally the same disorder and Brugada syndrome has been a subject of intensive study since its early description in 1992. While Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit. less than 20% of its patients are known to be associated with SCN5A mutations. Moreover, the postmortem molecular screening of SCN5A mutations on formalin fixed paraffin embbeded cardiac tissues from SMDS cases has not been rewarding due to technical problems. The role of structural heart disease and sodium channel dysfunction in the induction of electrical instability in SMDS and Brugada syndrome is still debatable.

Nav1.5 Na~+ Channels in Human Brain Are Encoded by New Variants of Nav1.5/SCN5A / 生物化学与生物物理进展

98% amino acid identity.There are 28 different amino acids between them,with 7 of which locating in the region encoded by exon6A or exon6.Alternative splicing of exon18 was not found in the gene cloning of human brain Nav1.5/SCN5A,which was different from human heart Nav1.5/SCN5A,but a novel alternative splicing lacking exon24 was first found.The two variants were detected in similar ratio in brain,but they were proved to relate to age development in heart tissue.The exon24 of human Nav1.5/SCN5A has 54 nucleotides,encoding 30 amino acid residues,and are located in human chromosome 3P21.This alternative splicing was also found in other tissues other than heart and brain.The expression pattern of the two variants in different tissues was different when detected by competitive PCR method and it was also changing with age development.Furthermore,Nav1.5/SCN5A mRNA was detected in 16 different tissue types of Wistar rats(P80) by reverse polymerase chain reaction(RT-PCR) .These results suggest that Nav1.5 Na+ channels in human brain are encoded by new variants of Nav1.5/SCN5A and its mRAN is more widely expressed than previously thought.The study is useful for making further investigation in the functional analysis of Nav1.5 Na+ channels in different tissues.

Studies on single nucleotide polymorphisms of SCN5A gene / 解放军医学杂志

C and C 5457T (D1819D) were 11.1%, 5.2%, 28.2% and 31.8%, respectively. The minor allele frequency of SNPs was not same as study from Japanese or Chinese. Conclusion The distribution of SCN5A SNPs may vary between different ethnicities.

Dependence analysis between sudden manhood death syndrome and mutation of SCN5A / 中国法医学杂志

In resent years, the accounts about adults' sudden death without specific reason have been increased. The definition of cause of death was a hot potato to legal medical experts. With the deep - going of etiology to molecular level, clinical cardiac diseases' researches have confirmed that the arrhythmia has been resulted from a kind of " idiopathic disorder of cardiac action potential" that is related to cardiac sodium channel diseases by SCN5A mutation confirmed by using the techniques of molecular genetics. The paper reviewed the characteristic of SMDS ( Sudden Manhood Death Syndrome) in forensic science and some kinds of diseases' genotype and phenotype in clinical medicine, and hoped to acquire some revelation for further related research.