Exploring SCN5A variants associated with atrial fibrillation in atrial cardiomyocytes derived from human induced pluripotent stem cells: A characterization study.

Background: Atrial fibrillation (AF) poses a major risk for heart failure, myocardial infarction, and stroke. Several studies have linked SCN5A variants to AF, but their precise mechanistic contribution remains unclear. Human induced pluripotent stem cells (hiPSCs) provide a promising platform for modeling AF-linked SCN5A variants and their functional alterations.

Generation of a patient-specific iPSC cell line with cardiac arrhythmias and dilated cardiomyopathy (CBRCULi016-A), an isogenic control (CBRCULi016-A-1), and a paternal control (CBRCULi017-A).

Dilated cardiomyopathy (DCM) is a prevalent cause of heart failure. We generated induced pluripotent stem cell (iPSC) lines from a DCM patient carrying a mutation in the SCN5A gene, with his healthy father serving as a control. Notably, we employed CRISPR-Cas9 to rectify the mutation in the patient's iPSC line.

De novo Y1460C missense variant in Na1.1 impedes the pore region and results in epileptic encephalopathy.

Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SCN1A encodes Na1.1, a neuronal voltage-gated Na channel that is highly expressed throughout the central nervous system.

-related epilepsy of infancy with migrating focal seizures: report of a variant with apparent gain- and loss-of-function effects.

SCN2A encodes a voltage-gated sodium channel (Na1.2) expressed throughout the central nervous system in predominantly excitatory neurons. Pathogenic variants in are associated with epilepsy and neurodevelopmental disorders.

Na1.5 knockout in iPSCs: a novel approach to study Na1.5 variants in a human cardiomyocyte environment.

Cardiomyocytes derived from patient-specific induced pluripotent stem cells (iPSC-CMs) successfully reproduce the mechanisms of several channelopathies. However, this approach involve cell reprogramming from somatic tissue biopsies or genomic editing in healthy iPSCs for every mutation found and to be investigated. We aim to knockout (KO) Na1.

iPSC-derived cardiomyocytes from patients with myotonic dystrophy type 1 have abnormal ion channel functions and slower conduction velocities.

Cardiac complications such as electrical abnormalities including conduction delays and arrhythmias are the main cause of death in individuals with Myotonic Dystrophy type 1 (DM1). We developed a disease model using iPSC-derived cardiomyocytes (iPSC-CMs) from a healthy individual and two DM1 patients with different CTG repeats lengths and clinical history (DM1-1300 and DM1-300). We confirmed the presence of toxic RNA foci and mis-spliced MBNL1/2 transcripts in DM1 iPSC-CMs.

R1617Q epilepsy mutation slows Na 1.6 sodium channel inactivation and increases the persistent current and neuronal firing.

Key Points: A human Na 1.6 construct was established to study the biophysical consequences of the R1617Q mutation on Na 1.6 identified in patients with unclassified epileptic encephalopathy and severe intellectual disability.

Differentiation of lymphoblastoid-derived iPSCs into functional cardiomyocytes, neurons and myoblasts.

Human induced pluripotent stem cells (hiPSCs) are a valuable tool for investigating complex cellular and molecular events that occur in several human diseases. Importantly, the ability to differentiate hiPSCs into any human cell type provides a unique way for investigating disease mechanisms such as complex mental health diseases. The in vitro transformation of human lymphocytes into lymphoblasts (LCLs) using the Epstein-Barr virus (EBV) has been the main method for generating immortalized human cell lines for half a century.

Substitutions of the S4DIV R2 residue (R1451) in Na1.4 lead to complex forms of paramyotonia congenita and periodic paralyses.

Mutations in Na1.4, the skeletal muscle voltage-gated Na channel, underlie several skeletal muscle channelopathies. We report here the functional characterization of two substitutions targeting the R1451 residue and resulting in 3 distinct clinical phenotypes.

A recessive Nav1.4 mutation underlies congenital myasthenic syndrome with periodic paralysis.

Objective: To determine the molecular basis of a complex phenotype of congenital muscle weakness observed in an isolated but consanguineous patient.

Methods: The proband was evaluated clinically and neurophysiologically over a period of 15 years. Genetic testing of candidate genes was performed.

Differential modulation of Nav1.7 and Nav1.8 channels by antidepressant drugs.

Antidepressant drugs of the SSRI family are used as a third-line treatment for neuropathic pain. In contrast MAOi antidepressants, that also increase extracellular serotonin bioavailability have little or no effects on this condition. In addition to their action of the serotonin transporter, some SSRI have been shown to inhibit voltage gated sodium channels.

Fluoxetine blocks Nav1.5 channels via a mechanism similar to that of class 1 antiarrhythmics.

The voltage-gated Nav1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases.

Pyridoxal-5'-phosphate (MC-1), a vitamin B6 derivative, inhibits expressed P2X receptors.

P2X receptors are cation-permeable ligand-gated ion channels that open in response to the binding of ATP. These receptors are present in many excitable cells, including neurons, striated muscle cells, epithelial cells, and leukocytes. They mediate fast excitatory neurotransmission in the central and peripheral nervous systems and are thought to be involved in neuropathic pain, inflammation, and cell damage following ischemia-reperfusion injuries.

Modulation of peripheral Na(+) channels and neuronal firing by n-butyl-p-aminobenzoate.

n-butyl-p-aminobenzoate (BAB), a local anesthetic, is administered epidurally in cancer patients to treat pain that is poorly controlled by other drugs that have a number of adverse effects. The purpose of the study was to unravel the mechanisms underlying the apparent selective pain suppressant effect of BAB. We used the whole-cell patch-clamp technique to record Na(+) currents and action potentials (APs) in dissociated, nociceptive dorsal root ganglion (DRG) cells from rats, two types of peripheral sensory neuron Na(+) channels (Nav1.

The variant hERG/R148W associated with LQTS is a mutation that reduces current density on co-expression with the WT.

Background: A variant of the ether-à-go-go related channel (hERG), p.Arg148Trp (R148W) was found at heterozygous state in two infants who died from sudden infant death syndrome (SIDS), one with documented prolonged QTc and Torsade de Pointes (TdP), and in an adult woman with QTc >500 ms, atrioventricular block and TdP. This variant was previously reported in cases of severe ventricular arrhythmia but very rarely in control subjects.

Serum- and glucocorticoid-regulated kinase 1 (SGK1) induction by the EWS/NOR1(NR4A3) fusion protein.

The NR4A3 nuclear receptor (also known as NOR1) is involved in tumorigenesis by the t(9;22) chromosome translocation encoding the EWS/NOR1 fusion protein found in approximately 75% of all cases of extraskeletal myxoid chondrosarcomas (EMC). Several observations suggest that one role of EWS/NOR1 in tumorigenesis may be to deregulate the expression of specific target genes. We have shown previously that constitutive expression of EWS/NOR1 in CFK2 fetal rat chondrogenic cells induces their transformation as measured by growth beyond confluency and growth in soft agar.

The PLAGL1 gene is down-regulated in human extraskeletal myxoid chondrosarcoma tumors.

In approximately 70% of human extraskeletal myxoid chondrosarcoma (EMC) tumors, a t(9;22) chromosome translocation gives rise to a fusion protein, named EWS/NOR1, containing the amino-terminal domain of EWS fused to the complete amino acid sequence of the nuclear receptor NOR1. Several observations suggest that one role of EWS/NOR1 in EMC may be to deregulate the expression of specific genes involved in the tumoral process. In order to identify these genes, we have used a CFK2 chondrogenic cell line over-expressing EWS/NOR1.