Ion Channel-related Genes Research Articles

Genetic characteristics of non-familial epilepsy.

BackgroundKnowledge of the genetic etiology of epilepsy can provide essential prognostic information and influence decisions regarding treatment and management, leading us into the era of precision medicine. However, the genetic basis underlying epileptogenesis or epilepsy pharmacoresistance is not well-understood, particularly in non-familial epilepsies with heterogeneous phenotypes that last until or start in adulthood.MethodsWe sought to determine the contribution of known epilepsy-associated genes (EAGs) to the causation of non-familial epilepsies with heterogeneous phenotypes and to the genetic basis underlying epilepsy pharmacoresistance. We performed a multi-center study for whole exome sequencing-based screening of 178 selected EAGs in 243 non-familial adult patients with primarily focal epilepsy (122 drug-resistant and 121 drug-responsive epilepsies). The pathogenicity of each variant was assessed through a customized stringent filtering process and classified according to the American College of Medical Genetics and Genomics guidelines.ResultsPossible causal genetic variants of epilepsy were uncovered in 13.2% of non-familial patients with primarily focal epilepsy. The diagnostic yield according to the seizure onset age was 25% (2/8) in the neonatal and infantile period, 11.1% (14/126) in childhood and 14.7% (16/109) in adulthood. The higher diagnostic yields were from ion channel-related genes and mTOR pathway-related genes, which does not significantly differ from the results of previous studies on familial or early-onset epilepsies. These potentially pathogenic variants, which were identified in genes that have been mainly associated with early-onset epilepsies with severe phenotypes, were also linked to epilepsies that start in or last until adulthood in this study. This finding suggested the presence of one or more disease-modifying factors that regulate the onset time or severity of epileptogenesis. The target hypothesis of epilepsy pharmacoresistance was not verified in our study. Instead, neurodevelopment-associated epilepsy genes, such as TSC2 or RELN, or structural brain lesions were more strongly associated with epilepsy pharmacoresistance.ConclusionsWe revealed a fraction of possible causal genetic variants of non-familial epilepsies in which genetic testing is usually overlooked. In this study, we highlight the importance of earlier identification of the genetic etiology of non-familial epilepsies, which leads us to the best treatment options in terms of precision medicine and to future neurobiological research for novel drug development. This should be considered a justification for physicians determining the hidden genetics of non-familial epilepsies that last until or start in adulthood.

Abstract 786: A Novel Desmoplakin Mutation Contributes to Arrhythmogenic Cardiomyopathy

Genetic alterations in desmosomal genes are associated with arrhythmogenic cardiomyopathy (ACM). This condition is characterized by sudden cardiac death, severe arrhythmias, and the presence of fibro-fatty patches within the myocardium. Despite the fact that the pathophysiology of ACM is well described, the molecular mechanisms underlying disease onset and progression are poorly understood. In an effort to identify disease-driving mechanisms we obtained induced pluripotent stem cells (hIPS) from a patient harboring a novel heterozygous mutation in desmoplakin ( DSP p.Tyr1188His/WT ), which we corrected to yield an isogenic control. hIPS cells carrying a known pathogenic mutation in desmoplakin ( DSP p.Arg1113X/WT ) served as a positive control. Gene expression analyses of DSP p.Tyr1188His/WT hIPS-derived cardiomyocytes revealed a dysregulation of desmosomal and ion channel-related genes. At the functional level we observed a prolonged action potential duration in DSP p.Tyr1188His/WT cardiomyocytes. Importantly, we validated these findings in an independent knock-in line carrying the same heterozygous ( DSP p.Tyr1188His/WT ) mutation. To study the in vivo relevance we additionally generated two corresponding mouse models harboring the mouse equivalent of the human desmoplakin mutations in the endogenous locus ( Dsp p.Tyr1200His/WT and Dsp p.Arg1125X/WT ). Both lines show altered connexin 43, phospholamban and Na V 1.5 expression levels under baseline conditions, recapitulating the changes observed in the hIPS-derived cardiomyocytes. Moreover, Fos- and RhoA-signaling pathways are enriched in these mice compared with wildtype littermates. Since exercise can be a trigger for the development of ACM, we are currently in the process of examining the effect of intense swimming exercise in the models. We show that the DSP p.Tyr1188His/WT mutation causes cellular changes linked to ACM pathogenesis, indicating this mutation to be disease-driving. Moreover, our novel mouse models of ACM recapitulate the findings observed in our human models and show key hallmarks of ACM disease progression. Future studies will focus on the underlying pathogenic mechanisms in the presented models.

The research of ion channel-related gene polymorphisms with atrial fibrillation in the Chinese Han population.

BackgroundAtrial fibrillation (AF) is one of the common arrhythmia in clinics. Its incidence is high among the elderly. This study aimed to identify a possible connection between ion channel‐related gene polymorphisms and the risk of AF.MethodsA total of 381 patients with coronary heart disease were recruited. Based on complete cardiac examination, the patients were divided into two subgroups: 185 patients with AF and 196 patients without AF. An association analysis was performed using 13 genotyped SNPs. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by conditional logistic regression.ResultsIn our research, we found that KCNE2 rs8134775 was associated with a decreased AF risk in the allele model (OR = 0.70; 95% CI: 0.50–0.97; p = 0.034). Genetic model analysis shown that the minor allele T of GJA5 rs35594137 was associated with a decreased AF risk under the recessive model (OR = 0.40; 95% CI: 0.19–0.86; p = 0.018) and the minor allele G of KCNJ2 rs8079702 was associated with an increased AF risk in the recessive model (OR = 2.31; 95% CI: 1.20–4.42; p = 0.012).ConclusionsOur results suggest that KCNE2, KCNJ2, and GJA5 influence the development of AF.

Identification of gene mutations in patients with primary periodic paralysis using targeted next-generation sequencing

BackgroundPrimary periodic paralysis is characterized by recurrent quadriplegia typically associated with abnormal serum potassium levels. The molecular diagnosis of primary PP previously based on Sanger sequencing of hot spots or exon-by-exon screening of the reported genes.MethodsWe developed a gene panel that includes 10 ion channel-related genes and 245 muscular dystrophy- and myopathy-related genes and used this panel to diagnose 60 patients with primary periodic paralysis and identify the disease-causing or risk-associated gene mutations.ResultsMutations of 5 genes were discovered in 39 patients (65.0%). SCN4A, KCNJ2 and CACNA1S variants accounted for 92.5% of the patients with a genetic diagnosis.ConclusionsTargeted next-generation sequencing offers a cost-effective approach to expand the genotypes of primary periodic paralysis. A clearer genetic profile enables the prevention of paralysis attacks, avoidance of triggers and the monitoring of complications.

NEXT GENERATION SEQUENCING AND EXPERIMENTAL MYOLOGY: P.374Identification of gene mutations in patients with primary periodic paralysis using targeted next-generation sequencing

Primary periodic paralysis comprises rare skeletal ion channelopathies characterized by recurrent quadriplegia typically associated with high or low serum potassium levels. We developed a gene panel that includes 10 ion channel-related genes and 245 muscular dystrophy- and myopathy-related genes and used this panel to diagnose 60 patients with primary periodic paralysis and identify the disease-causing or risk-associated gene mutations. The average sequencing depth using this panel was 488.11 ×, and the average coverage was 99.45%. Mutations in 5 genes were discovered in 40 patients (66.67%). Variants in SCN4A, KCNJ2 and CACNA1S genes accounted for 92.5% of the patients with a genetic diagnosis. SCN4A (NM_000334) mutations accounted for the majority in this primary PP cohort (47.5%). We identified 10 SCN4A variants including 5 reported mutations (c.2014C>T p.Arg672Cys, c.2024G>A p.Arg675Gln, c.2111C>T p.Thr704Met, c.4352G>T p.Arg1451Leu, and c.4774A>G p.Met1592Val) and 5 novel mutations (c.107_109del p.Glu36del, c.121C>T p.Arg41Trp, c.718G>A p.Val240Met, c.3868T>C p.Phe1290Leu and c.5293G>A p.Ala1765Thr). Among them, c.2024G>A p.Arg675Gln was identified in 8 patients from 6 families as a hotspot. KCNJ2 is the second most common genetic cause.We identified 9 reported variants (c.199C>T p.Arg67Trp, c.211G>A p.Asp71Asn, c.556C>A p.Pro186Thr, c.566G>T p.Arg189Ser, c.644G>A p.Gly215Asp, c.652C>T p.Arg218Trp, c. 899G>A p.Gly300Asp, c.919A>G p.Met307Val, and c.921G>C p.Met307Ile) in a total of 14 patients. Moreover, we identified 4 likely pathogenic variants (c.614T>A p.Phe205Tyr, c.1583G>A p.Arg528His, c.2965G>A p.Glu989Lys and c.3716G>A p.Arg1239His) in CACNA1S gene (NM_000069). Two RYR1 variants (p.Glu2764Lys and p.Ala4143Val) were identified in this cohort, together with one reported OPA1 variant (p.Ala357Thr) which is previously responsible for optic atrophy related phenotypes. Using targeted NGS, we achieved a diagnostic success rate of 66.67% in a cohort of primary PP patients. We expanded the spectrum of genotypes of primary PP and clinical phenotypes of known myopathy-related genes. We'd like to attribute this diagnostic rate to the inclusive strategy of screening for other causal factors of hypokalaemic muscle weakness and performing accurate clinical examinations and history inquiries prior to interpreting the NGS results.

Long QT Syndrome and Sinus Bradycardia-A Mini Review.

Congenital long-QT syndrome (LQTS) is an inherited cardiac disorder characterized by the prolongation of ventricular repolarization, susceptibility to Torsades de Pointes (TdP), and a risk for sudden death. Various types of congenital LQTS exist, all due to specific defects in ion channel-related genes. Interestingly, almost all of the ion channels affected by the various types of LQTS gene mutations are also expressed in the human sinoatrial node (SAN). It is therefore not surprising that LQTS is frequently associated with a change in basal heart rate (HR). However, current data on how the LQTS-associated ion channel defects result in impaired human SAN pacemaker activity are limited. In this mini-review, we provide an overview of known LQTS mutations with effects on HR and the underlying changes in expression and kinetics of ion channels. Sinus bradycardia has been reported in relation to a large number of LQTS mutations. However, the occurrence of both QT prolongation and sinus bradycardia on a family basis is almost completely limited to LQTS types 3 and 4 (LQT3 and Ankyrin-B syndrome, respectively). Furthermore, a clear causative role of this sinus bradycardia in cardiac events seems reserved to mutations underlying LQT3.

Differential left-to-right atria gene expression ratio in human sinus rhythm and atrial fibrillation: Implications for arrhythmogenesis and thrombogenesis

BackgroundAtrial fibrillation (AF) causes atrial remodeling, and the left atrium (LA) is the favored substrate for maintaining AF. It remains unclear if AF remodels both atria differently and contributes to LA arrhythmogenesis and thrombogenesis. Therefore, we wished to characterize the transcript profiles in the LA and right atrium (RA) in sinus rhythm (SR) and AF respectively. MethodsPaired LA and RA appendages acquired from patients receiving cardiac surgery were used for ion-channel- and whole-exome-based transcriptome analysis. The ultrastructure was evaluated by immunohistochemistry. ResultsTwenty-two and twenty ion-channels and transporters were differentially expressed between the LA and RA in AF and SR, respectively. Among these, 15 genes were differentially expressed in parallel between AF and SR. AF was associated with increased LA/RA expression ratio in 9 ion channel-related genes, including genes related to calcium handling. In microarray, AF was associated with a differential LA/RA gene expression ratio in 309 genes, and was involved in atherosclerosis-related signaling. AF was associated with the upregulation of thrombogenesis-related genes in the LA appendage, including P2Y12, CD 36 and ApoE. Immunohistochemistry showed higher expressions of collagen-1, oxidative stress and TGF-β1 in the RA compared to the LA. ConclusionsAF was associated with differential LA-to-RA gene expression related to specific ion channels and pathways as well as upregulation of thrombogenesis-related genes in the LA appendage. Targeting the molecular mechanisms underlying the LA-to-RA difference and AF-related remodeling in the LA appendage may help provide new therapeutic options in treating AF and preventing thromboembolism in AF.

Large-scale analysis of brain-wide electrophysiological diversity reveals novel characterization of mammalian neuron types

Brains achieve efficient function through implementing a division of labor, in which different neurons serve distinct computational roles. One striking way in which neuron types differ is in their electrophysiology properties. These properties arise through expression of combinations of ion channels that collectively define the computations that a neuron performs on its inputs and its role within its larger circuit. Though the electrophysiology of many neuron types has been previously characterized, these data exist across thousands of journal articles, making cross-study neuron-to-neuron comparisons difficult. Here, we present NeuroElectro, a public database where physiological properties for the majority of mammalian neuron types have been compiled through semi-automated literature text-mining and expert curation. The corresponding web application, at http://www.neuroelectro.org, provides a rich dynamic interface for visualizing and comparing physiological information across neuron types; conveniently linking extracted data back to its primary reference. Mining the database content after normalization for methodological differences, we show that there exist but 5-9 major neuron classes in terms of electrophysiological properties, which separate largely based on cell size and basal levels of excitability (Figure ​(Figure11). Figure 1 Hierarchical clustering of diverse neuron types on the basis of electrophysiological similarity. Electrophysiological parameters are obtained from the NeuroElectro database via literature-mining and are normalized to account for variability in experimental ... As an example of how this resource can help answer fundamental questions in neuroscience, we integrate NeuroElectro with neuronal gene expression from public datasets like the Allen Brain Atlas. We show that simple statistical models can accurately predict features of a neuron's electrophysiological phenotype given information of its gene expression alone. We further investigate these models to ask which genes, of the 20K in the genome, are most predictive of neuron physiology. We find that while ion channel-related genes provide significant predictive power, the most predictive gene classes surprisingly correspond to G-proteins and transcription factors, suggesting the involvement of hundreds of diverse genes in regulating a neuron's computational function.

A note on the prevalence of cardiac ion channelopathies in the sudden infant death syndrome

In the December 2014 issue of Europace , Wong and Behr1 published a review on the role of undiagnosed inherited cardiac conditions in sudden unexplained death in infants and children, which I read with great interest. In their Table 1, Wong and Behr1 provide the reader with data on the frequency of mutations in ion channel-related genes in cases of sudden infant death syndrome (SIDS). For example, a frequency of 1.0% is listed for mutations in the KCNQ1 gene, with reference to three studies on cohorts of SIDS cases (their references 30–32, which I cannot repeat here because of the restrictions …

P-30 * ETHANOL-INDUCED EXPRESSION OF ION CHANNELS IN RAT BRAIN SLICES

Chronic alcohol consumption affects brain functions such as learning, memory and motor skills, which constitute signal transduction, neural transmission, and ion channels. However, any roles of ethanol in expression of ion channels in the brain have never been clarified. In this study, we evaluated the effects of ethanol on the mRNA expression of ion channels in the rat brain slices. The experiment with organotypic brain slice cultures was performed to examine the effects of ethanol on various genes expression. Wistar male rats (8 weeks old) were anesthetized by carbon dioxide and immediately decapitated. After brain dissection, the frontal and occipital poles including the cerebellum were removed, and then the specimens were sliced into 0.2 mm thick sections on a tissue slicer. Three hours after culture, the slice was incubated in the medium with or without 50-mM ethanol for 12 hours. RNA was isolated from the slice by TRIzol. The expression of various mRNAs in the RNA samples was revealed by a quantitative real-time RT-PCR system. Ethanol treatment significantly increased the expression of ion channel related genes compared as non-treatment with ethanol. Therefore these findings suggest that expression of ion channels will cause ethanol- induced brain dysfunction.

Transcriptional profiling reveals ductus arteriosus-specific genes that regulate vascular tone.

Failure of the ductus arteriosus (DA) to close at birth can lead to serious complications. Conversely, certain profound congenital cardiac malformations require the DA to be patent until corrective surgery can be performed. In each instance, clinicians have a very limited repertoire of therapeutic options at their disposal - indomethacin or ibuprofen to close a patent DA (PDA) and prostaglandin E1 to maintain patency of the DA. Neither treatment is specific to the DA and both may have deleterious off-target effects. Therefore, more therapeutic options specifically targeted to the DA should be considered. We hypothesized the DA possesses a unique genetic signature that would set it apart from other vessels. A microarray was used to compare the genetic profiles of the murine DA and ascending aorta (AO). Over 4,000 genes were differentially expressed between these vessels including a subset of ion channel-related genes. Specifically, the alpha and beta subunits of large-conductance calcium-activated potassium (BKCa) channels are enriched in the DA. Gain- and loss-of-function studies showed inhibition of BKCa channels caused the DA to constrict, while activation caused DA relaxation even in the presence of O2. This study identifies subsets of genes that are enriched in the DA that may be used to develop DA-specific drugs. Ion channels that regulate DA tone, including BKCa channels, are promising targets. Specifically, BKCa channel agonists like NS1619 maintain DA patency even in the presence of O2 and may be clinically useful.

EKG Pattern of Brugada Syndrome and Sudden Infant Death Syndrome—Is It Time to Review the Diagnostic Criteria? Case Report and Review of Literature

Brugada Syndrome (BrS) is a cardiac disorder characterized by incomplete right bundle-branch block and ST elevations in the anterior precordial leads especially V1 -V3 , associated with an increased risk for sudden cardiac death (SCD) in young adults. Our case describes a patient with family history of sudden infant death syndrome (SIDS) who presented with a Brugada pattern unmasked by severe hyperkalemia and diabetic ketoacidosis. Several studies have concluded there may be a genetic link among SIDS, SDC, and BrS resulting from mutations in cardiac ion channel-related genes. Recognizing SIDS as part of the diagnostic criteria for BrS would help us identifying a significant number of families susceptible to develop SCD (as well as SIDS).

Cardiac ion channelopathies and the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) causes the sudden death of an apparently healthy infant, which remains unexplained despite a thorough investigation, including the performance of a complete autopsy. The triple risk model for the pathogenesis of SIDS points to the coincidence of a vulnerable infant, a critical developmental period, and an exogenous stressor. Primary electrical diseases of the heart, which may cause lethal arrhythmias as a result of dysfunctioning cardiac ion channels (“cardiac ion channelopathies”) and are not detectable during a standard postmortem examination, may create the vulnerable infant and thus contribute to SIDS. Evidence comes from clinical correlations between the long QT syndrome and SIDS as well as genetic analyses in cohorts of SIDS victims (“molecular autopsy”), which have revealed a large number of mutations in ion channel-related genes linked to inheritable arrhythmogenic syndromes, in particular the long QT syndrome, the short QT syndrome, the Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Combining data from population-based cohort studies, it can be concluded that at least one out of five SIDS victims carries a mutation in a cardiac ion channel-related gene and that the majority of these mutations are of a known malignant phenotype.

Genome-Wide DNA Methylation and Gene Expression Analyses of Monozygotic Twins Discordant for Intelligence Levels

Human intelligence, as measured by intelligence quotient (IQ) tests, demonstrates one of the highest heritabilities among human quantitative traits. Nevertheless, studies to identify quantitative trait loci responsible for intelligence face challenges because of the small effect sizes of individual genes. Phenotypically discordant monozygotic (MZ) twins provide a feasible way to minimize the effects of irrelevant genetic and environmental factors, and should yield more interpretable results by finding epigenetic or gene expression differences between twins. Here we conducted array-based genome-wide DNA methylation and gene expression analyses using 17 pairs of healthy MZ twins discordant intelligently. ARHGAP18, related to Rho GTPase, was identified in pair-wise methylation status analysis and validated via direct bisulfite sequencing and quantitative RT-PCR. To perform expression profile analysis, gene set enrichment analysis (GSEA) between the groups of twins with higher IQ and their co-twins revealed up-regulated expression of several ribosome-related genes and DNA replication-related genes in the group with higher IQ. To focus more on individual pairs, we conducted pair-wise GSEA and leading edge analysis, which indicated up-regulated expression of several ion channel-related genes in twins with lower IQ. Our findings implied that these groups of genes may be related to IQ and should shed light on the mechanism underlying human intelligence.

Gene expression of fibroblasts following light irradiation

Gene expression of fibroblasts following light irradiation