Gene Expression In Drosophila Hearts Harboring Ion Channel Mutations
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE94589 | GEO | 2017/04/01
SECONDARY ACCESSION(S): PRJNA371552
REPOSITORIES: GEO
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Project description:BackgroundVentricular tachyarrhythmias and sudden cardiac death show a circadian pattern of occurrence in patients with heart failure. In the rodent ventricle, a significant portion of genes, including some ion channels, shows a circadian pattern of expression. However, genes that define electrophysiological properties in failing human heart ventricles have not been examined for a circadian expression pattern.MethodsVentricular tissue samples were collected from patients at the time of cardiac transplantation. Two sets of samples (n=37 and 46, one set with a greater arrhythmic history) were selected to generate pseudo-time series according to their collection time. A third set (n=27) of samples was acquired from the nonfailing ventricles of brain-dead donors. The expression of 5 known circadian clock genes and 19 additional ion channel genes plausibly important to electrophysiological properties were analyzed by real-time polymerase chain reaction and then analyzed for the percentage of expression variation attributed to a 24-hour circadian pattern.ResultsThe 5 known circadian clock gene transcripts showed a strong circadian expression pattern. Compared with rodent hearts, the human circadian clock gene transcripts showed a similar temporal order of acrophases but with a ≈7.6 hours phase shift. Five of the ion channel genes also showed strong circadian expression. Comparable studies of circadian clock gene expression in samples recovered from nonheart failure brain-dead donors showed acrophase shifts, or weak or complete loss of circadian rhythmicity, suggesting alterations in circadian gene expression.ConclusionsVentricular tissue from failing human hearts display a circadian pattern of circadian clock gene expression but phase-shifted relative to rodent hearts. At least 5 ion channels show a circadian expression pattern in the ventricles of failing human hearts, which may underlie a circadian pattern of ventricular tachyarrhythmia/sudden cardiac death. Nonfailing hearts from brain-dead donors show marked differences in circadian clock gene expression patterns, suggesting fundamental deviations from circadian expression.
| S-EPMC7875252 | biostudies-literature
Project description:Transcriptional profiling of Indy long lived flies and controls over the course of their entire lifespan. Mutations in the Indy gene extend life span in Drosophila melanogaster. This study investigates the changes in gene expression over time in Indy206 flies heterozygous over Canton-S (Indy206/CS) and compares them to genetically matched heterozygous controls (2216/CS). Samples from both fly strains were collected at age: 5, 10, 20, 30, 40, 50, 70 and 80.
2009-03-08 | GSE13872 | GEO
Project description:RationaleStructural differences between ventricular regions may not be the sole determinant of local ventricular fibrillation (VF) dynamics and molecular remodeling may play a role.ObjectivesTo define regional ion channel expression in myopathic hearts compared to normal hearts, and correlate expression to regional VF dynamics.Methods and resultsHigh throughput real-time RT-PCR was used to quantify the expression patterns of 84 ion-channel, calcium cycling, connexin and related gene transcripts from sites in the LV, septum, and RV in 8 patients undergoing transplantation. An additional eight non-diseased donor human hearts served as controls. To relate local ion channel expression change to VF dynamics localized VF mapping was performed on the explanted myopathic hearts right adjacent to sampled regions. Compared to non-diseased ventricles, significant differences (p<0.05) were identified in the expression of 23 genes in the myopathic LV and 32 genes in the myopathic RV. Within the myopathic hearts significant regional (LV vs septum vs RV) expression differences were observed for 13 subunits: Nav1.1, Cx43, Ca3.1, Cavα2δ2, Cavβ2, HCN2, Na/K ATPase-1, CASQ1, CASQ2, RYR2, Kir2.3, Kir3.4, SUR2 (p<0.05). In a subset of genes we demonstrated differences in protein expression between control and myopathic hearts, which were concordant with the mRNA expression profiles for these genes. Variability in the expression of Cx43, hERG, Na(+)/K(+) ATPase ß1 and Kir2.1 correlated to variability in local VF dynamics (p<0.001). To better understand the contribution of multiple ion channel changes on VF frequency, simulations of a human myocyte model were conducted. These simulations demonstrated the complex nature by which VF dynamics are regulated when multi-channel changes are occurring simultaneously, compared to known linear relationships.ConclusionsIon channel expression profile in myopathic human hearts is significantly altered compared to normal hearts. Multi-channel ion changes influence VF dynamic in a complex manner not predicted by known single channel linear relationships.
| S-EPMC3888386 | biostudies-literature
Project description:After an electrically induced seizure, mice (NMRI) received electrical stimulation (current intensity 44 mA, 0.2 ms monopolar pulses at 6 Hz frequency for 3 s). RNA was extracted from the hippocampi at 0, 3, 6, 24 and 72 h after the seizure. microRNA expressions were measured via microarray technology using Exiqon's miCURY™ LNA Arrays.
2014-01-01 | GSE51840 | GEO
Project description:After an electrically induced seizure, mice (NMRI) received electrical stimulation (current intensity 44 mA, 0.2 ms monopolar pulses at 6 Hz frequency for 3 s). RNA was extracted from the hippocampi at 0, 3, 6, 24 and 72 h after the seizure. microRNA expressions were measured via microarray technology using Exiqon's miCURY™ LNA Arrays. Time-course design, treated cells at 0, 3, 6, 24, and 72 h, with 7 replicate each
2014-01-01 | E-GEOD-51840 | biostudies-arrayexpress
Project description:The intracellular fibroblast growth factors (iFGF/FHFs) bind directly to cardiac voltage gated Na+ channels, and modulate their function. Mutations that affect iFGF/FHF-Na+ channel interaction are associated with arrhythmia syndromes. Although suspected to modulate other ionic currents, such as Ca2+ channels based on acute knockdown experiments in isolated cardiomyocytes, the in vivo consequences of iFGF/FHF gene ablation on cardiac electrical activity are still unknown. We generated inducible, cardiomyocyte-restricted Fgf13 knockout mice to determine the resultant effects of Fgf13 gene ablation. Patch clamp recordings from ventricular myocytes isolated from Fgf13 knockout mice showed a ~25% reduction in peak Na+ channel current density and a hyperpolarizing shift in steady-state inactivation. Electrocardiograms on Fgf13 knockout mice showed a prolonged QRS duration. The Na+ channel blocker flecainide further prolonged QRS duration and triggered ventricular tachyarrhythmias only in Fgf13 knockout mice, suggesting that arrhythmia vulnerability resulted, at least in part, from a loss of functioning Na+ channels. Consistent with these effects on Na+ channels, action potentials in Fgf13 knockout mice, compared to Cre control mice, exhibited slower upstrokes and reduced amplitude, but unexpectedly had longer durations. We investigated candidate sources of the prolonged action potential durations in myocytes from Fgf13 knockout mice and found a reduction of the transient outward K+ current (Ito). Fgf13 knockout did not alter whole-cell protein levels of Kv4.2 and Kv4.3, the Ito pore-forming subunits, but did decrease Kv4.2 and Kv4.3 at the sarcolemma. No changes were seen in the sustained outward K+ current or voltage-gated Ca2+ current, other candidate contributors to the increased action potential duration. These results implicate that FGF13 is a critical cardiac Na+ channel modulator and Fgf13 knockout mice have increased arrhythmia susceptibility in the setting of Na+ channel blockade. The unanticipated effect on Ito revealed new FGF13 properties and the unexpected lack of an effect on voltage-gated Ca2+ channels highlight potential compensatory changes in vivo not readily revealed with acute Fgf13 knockdown in cultured cardiomyocytes.
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Project description:Glioblastoma Multiforme (GBM) is the most common and invasive astrocytic tumor associated with dismal prognosis. Treatment for GBM patients has advanced, but the median survival remains a meager 15 months. In a recent study, 20,000 genes from 21 GBM patients were sequenced that identified frequent mutations in ion channel genes. The goal of this study was to determine whether ion channel mutations have a role in disease progression and whether molecular targeting of ion channels is a promising therapeutic strategy for GBM patients. Therefore, we compared GBM patient survival on the basis of presence or absence of mutations in calcium, potassium and sodium ion transport genes. Cardiac glycosides, known sodium channel inhibitors, were then tested for their ability to inhibit GBM cell proliferation.Nearly 90% of patients showed at least one mutation in ion transport genes. GBM patients with mutations in sodium channels showed a significantly shorter survival compared to patients with no sodium channel mutations, whereas a similar comparison based on mutational status of calcium or potassium ion channel mutations showed no survival differences. Experimentally, targeting GBM cells with cardiac glycosides such as digoxin and ouabain demonstrated preferential cytotoxicity against U-87 and D54 GBM cells compared to non-tumor astrocytes (NTAs).These pilot studies of GBM patients with sodium channel mutations indicate an association with a more aggressive disease and significantly shorter survival. Moreover, inhibition of GBM cells by ion channel inhibitors such as cardiac glycosides suggest a therapeutic strategy with relatively safe drugs for targeting GBM ion channel mutations. Key Words: glioblastoma multiforme, ion channels, mutations, small molecule inhibitors, cardiac glycosides.
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Project description:In this study, we combined linkage analysis with whole-exome sequencing of two individuals to identify candidate causal variants in a moderately-sized UK kindred exhibiting autosomal-dominant inheritance of craniocervical dystonia. Subsequent screening of these candidate causal variants in a large number of familial and sporadic cases of cervical dystonia led to the identification of a total of six putatively pathogenic mutations in ANO3, a gene encoding a predicted Ca(2+)-gated chloride channel that we show to be highly expressed in the striatum. Functional studies using Ca(2+) imaging in case and control fibroblasts demonstrated clear abnormalities in endoplasmic-reticulum-dependent Ca(2+) signaling. We conclude that mutations in ANO3 are a cause of autosomal-dominant craniocervical dystonia. The locus DYT23 has been reserved as a synonym for this gene. The implication of an ion channel in the pathogenesis of dystonia provides insights into an alternative mechanism that opens fresh avenues for further research.
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Project description:Cardiac ion channelopathies are an important cause of sudden death in the young and include long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, and short QT syndrome. Genes that encode ion channels have been implicated in all of these conditions, leading to the widespread implementation of genetic testing for suspected channelopathies. Over the past half-century, researchers have also identified systemic pathologies that extend beyond the arrhythmic phenotype in patients with ion channel gene mutations, including deafness, epilepsy, cardiomyopathy, periodic paralysis, and congenital heart disease. A coexisting phenotype, such as cardiomyopathy, can influence evaluation and management. However, prior to recent molecular advances, our understanding and recognition of these overlapping phenotypes were poor. This review highlights the systemic and structural heart manifestations of the cardiac ion channelopathies, including their phenotypic spectrum and molecular basis.
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Project description:Transcranial Electrical Stimulation has therapeutic effects on different diseases, including epilepsy. Particularly, Transcranial Focal Stimulation (TFS) has anticonvulsive and antiepileptogenic effects. Nevertheless, the mechanisms and therapeutic targets that induced these effects remain ellusive. We aimed to screen the genetic expression in the cerebral cortex and the hippocampus of rats after a single seizure and TFS to identify potential targets.
2024-03-30 | GSE199183 | GEO