Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Defining a new paradigm for human arrhythmia syndromes: phenotypic manifestations of gene mutations in ion channel- and transporter-associated proteins.

ABSTRACT: Over the past 15 years, gene mutations in cardiac ion channels have been linked to a host of potentially fatal human arrhythmias including long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. More recently, a new paradigm for human arrhythmia has emerged based on gene mutations that affect the activity of cardiac ion channel- and transporter- associated proteins. As part of the Circulation Research thematic series on inherited arrhythmias, this review focuses on the emerging field of human arrhythmias caused by dysfunction in cytosolic gene products (including ankyrins, yotiao, syntrophin, and caveolin-3) that regulate the activities of key membrane ion channels and transporters.

SUBMITTER: Ackerman MJ

PROVIDER: S-EPMC2930837 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Defining a new paradigm for human arrhythmia syndromes: phenotypic manifestations of gene mutations in ion channel- and transporter-associated proteins.

Ackerman Michael J MJ Mohler Peter J PJ

Circulation research 20100801 4

Over the past 15 years, gene mutations in cardiac ion channels have been linked to a host of potentially fatal human arrhythmias including long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. More recently, a new paradigm for human arrhythmia has emerged based on gene mutations that affect the activity of cardiac ion channel- and transporter- associated proteins. As part of the Circulation Research thematic series on inherited arrhythm ...[more]

PMID: 20724725

Similar Datasets

Further Defining the Phenotypic Spectrum of B3GAT3 Mutations and Literature Review on Linkeropathy Syndromes.

Project description:The term linkeropathies (LKs) refers to a group of rare heritable connective tissue disorders, characterized by a variable degree of short stature, skeletal dysplasia, joint laxity, cutaneous anomalies, dysmorphism, heart malformation, and developmental delay. The LK genes encode for enzymes that add glycosaminoglycan chains onto proteoglycans via a common tetrasaccharide linker region. Biallelic variants in XYLT1 and XYLT2, encoding xylosyltransferases, are associated with Desbuquois dysplasia type 2 and spondylo-ocular syndrome, respectively. Defects in B4GALT7 and B3GALT6, encoding galactosyltransferases, lead to spondylodysplastic Ehlers-Danlos syndrome (spEDS). Mutations in B3GAT3, encoding a glucuronyltransferase, were described in 25 patients from 12 families with variable phenotypes resembling Larsen, Antley-Bixler, Shprintzen-Goldberg, and Geroderma osteodysplastica syndromes. Herein, we report on a 13-year-old girl with a clinical presentation suggestive of spEDS, according to the 2017 EDS nosology, in whom compound heterozygosity for two B3GAT3 likely pathogenic variants was identified. We review the spectrum of B3GAT3-related disorders and provide a comparison of all LK patients reported up to now, highlighting that LKs are a phenotypic continuum bridging EDS and skeletal disorders, hence offering future nosologic perspectives.

| S-EPMC6770791 | biostudies-literature

Gene Expression In Drosophila Hearts Harboring Ion Channel Mutations

Project description:Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations Sei and KCNQ mutants were compared to their control lines, Canton S-CS and KCNQ370

2017-04-01 | GSE94589 | GEO

Atypical Skin Manifestations in <i>FGFR2</i>-Related Craniosynostosis Syndromes Broaden the Phenotypic Spectrum.

Project description:Crouzon syndrome (CS) and Beare-Stevenson syndrome (BSS) are craniosynostosis syndromes caused by mutations in the fibroblast growth factor 2 (FGFR2) gene. CS is more common (1 in 60,000 live births) than BSS, where fewer than 20 individuals have been reported. The cardinal features of BSS are craniosynostosis, cutis gyrata, acanthosis nigricans, skin furrows, skin tags, anogenital anomalies, and a prominent umbilical stump. Previously described individuals with BSS have typically had mutations in exon 11 of FGFR2. Here, we present 2 patients with CS who have significant skin manifestations and some phenotypic overlap with BSS. De novo mutations in exon 8 of FGFR2 were identified in both; one is a mutation (c.799T>C; p.Ser267Pro) previously identified in individuals with CS and the other a novel in-frame deletion (c.820_824delinsTT; p.Val274_Glu275delinsLeu). No mutations in exon 11 of FGFR2, where previously reported BSS mutations have been located, were identified. This case expands the phenotypic spectrum of CS and highlights the overlap between conditions caused by mutations in FGFR2.

| S-EPMC6006653 | biostudies-literature

Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms.

Project description:The cardiac sodium channel NaV1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias. Yet, some NaV1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective NaV1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the NaV1.5 complex. In this alternative view, alterations in NaV1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of NaV1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through NaV1.5 on membrane potential and consequent action potential generation, (ii) indirect ionic effects of sodium influx on intracellular homeostasis and signalling, and (iii) non-ionic effects of NaV1.5, independent of sodium influx, through interactions with macromolecular complexes within the different microdomains of the cardiomyocyte. These indirect ionic and non-ionic processes may, acting alone or in concert, contribute significantly to arrhythmogenesis. Hence, further exploration of these multifunctional effects of NaV1.5 is essential for the development of novel preventive and therapeutic strategies.

| S-EPMC7341171 | biostudies-literature

Calmodulinopathy in inherited arrhythmia syndromes.

Project description:Calmodulin (CaM) is a ubiquitous intracellular calcium sensor that controls and regulates key cellular functions. In all vertebrates, three CaM genes located on separate chromosomes encode an identical 149 amino acid protein, implying an extraordinarily high level of evolutionary importance and suggesting that CaM mutations would be possibly fatal. Inherited arrhythmia syndromes comprise a spectrum of primary electrical disorders caused by mutations in genes encoding ion channels or associated proteins leading to various cardiac arrhythmias, unexplained syncope, and sudden cardiac death. CaM mutations have emerged as an independent entity among inherited arrhythmia syndromes, referred to as calmodulinopathies. The most common clinical presentation associated with calmodulinopathy is congenital long QT syndrome, followed by catecholaminergic polymorphic ventricular tachycardia, both of which significantly increase the possibility of repeated syncope, lethal arrhythmic events, and sudden cardiac death, especially in young individuals. Here, we aim to give an overview of biochemical and structural characteristics of CaM and progress toward updating current known CaM mutations and associated clinical phenotypes. We also review the possible mechanisms underlying calmodulinopathy, based on several key in vitro studies. We expect that further experimental studies are needed to explore the complexity of calmodulinopathy.

| S-EPMC8532581 | biostudies-literature

Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.

Project description:Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (CaV1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS.

| S-EPMC1149428 | biostudies-literature

Regulation of Ion Channel and Transporter Function Through RNA Editing.

Project description:A large proportion of the recoding events mediated by RNA editing are in mRNAs that encode ion channels and transporters. The effects of these events on protein function have been characterized in only a few cases. In even fewer instances are the mechanistic underpinnings of these effects understood. This review focuses on how RNA editing affects protein function and higher order physiology. In mammals, particular attention is given to the GluA2, an ionotropic glutamate receptor subunit, and K(v) 1.1, a voltage-dependent K+ channel, because they are particularly well understood. In K(v) addition, work on cephalopod K+ channels and Na+/K+-ATPases has also provided important clues on the rules used by RNA editing to regulate excitability. Finally, we discuss some of the emerging targets for editing and how this process may be used to regulate nervous function in response to a variable environment.

| S-EPMC5248560 | biostudies-literature

Phospholipid scrambling induced by an ion channel/metabolite transporter complex.

Project description:Cells establish the asymmetrical distribution of phospholipids and alter their distribution by phospholipid scrambling (PLS) to adapt to environmental changes. Here, we demonstrate that a protein complex, consisting of the ion channel Tmem63b and the thiamine transporter Slc19a2, induces PLS upon calcium (Ca2+) stimulation. Through revival screening using a CRISPR sgRNA library on high PLS cells, we identify Tmem63b as a PLS-inducing factor. Ca2+ stimulation-mediated PLS is suppressed by deletion of Tmem63b, while human disease-related Tmem63b mutants induce constitutive PLS. To search for a molecular link between Ca2+ stimulation and PLS, we perform revival screening on Tmem63b-overexpressing cells, and identify Slc19a2 and the Ca2+-activated K+ channel Kcnn4 as PLS-regulating factors. Deletion of either of these genes decreases PLS activity. Biochemical screening indicates that Tmem63b and Slc19a2 form a heterodimer. These results demonstrate that a Tmem63b/Slc19a2 heterodimer induces PLS upon Ca2+ stimulation, along with Kcnn4 activation.

| S-EPMC11366033 | biostudies-literature

Different arrhythmia-associated calmodulin mutations have distinct effects on cardiac SK channel regulation.

Project description:Calmodulin (CaM) plays a critical role in intracellular signaling and regulation of Ca2+-dependent proteins and ion channels. Mutations in CaM cause life-threatening cardiac arrhythmias. Among the known CaM targets, small-conductance Ca2+-activated K+ (SK) channels are unique, since they are gated solely by beat-to-beat changes in intracellular Ca2+. However, the molecular mechanisms of how CaM mutations may affect the function of SK channels remain incompletely understood. To address the structural and functional effects of these mutations, we introduced prototypical human CaM mutations in human induced pluripotent stem cell-derived cardiomyocyte-like cells (hiPSC-CMs). Using structural modeling and molecular dynamics simulation, we demonstrate that human calmodulinopathy-associated CaM mutations disrupt cardiac SK channel function via distinct mechanisms. CaMD96V and CaMD130G mutants reduce SK currents through a dominant-negative fashion. By contrast, specific mutations replacing phenylalanine with leucine result in conformational changes that affect helix packing in the C-lobe, which disengage the interactions between apo-CaM and the CaM-binding domain of SK channels. Distinct mutant CaMs may result in a significant reduction in the activation of the SK channels, leading to a decrease in the key Ca2+-dependent repolarization currents these channels mediate. The findings in this study may be generalizable to other interactions of mutant CaMs with Ca2+-dependent proteins within cardiac myocytes.

| S-EPMC7681919 | biostudies-literature

Calcium Handling Defects and Cardiac Arrhythmia Syndromes.

Project description:Calcium ions (Ca2+) play a major role in the cardiac excitation-contraction coupling. Intracellular Ca2+ concentration increases during systole and falls in diastole thereby determining cardiac contraction and relaxation. Normal cardiac function also requires perfect organization of the ion currents at the cellular level to drive action potentials and to maintain action potential propagation and electrical homogeneity at the tissue level. Any imbalance in Ca2+ homeostasis of a cardiac myocyte can lead to electrical disturbances. This review aims to discuss cardiac physiology and pathophysiology from the elementary membrane processes that can cause the electrical instability of the ventricular myocytes through intracellular Ca2+ handling maladies to inherited and acquired arrhythmias. Finally, the paper will discuss the current therapeutic approaches targeting cardiac arrhythmias.

| S-EPMC7052815 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data