scn10a

In the human genome, heterozygous sites refer to genomic positions with a different allele or nucleotide variant on the maternal and paternal chromosomes. Resolving these allelic differences by chromosomal copy, also known as phasing, is achievable on a short-read sequencer when using a library preparation method that captures long-range genomic information. TELL-Seq is a library preparation that captures long-range genomic information with the aid of molecular identifiers (barcodes). The same barcode is used to tag the reads derived from the same long DNA fragment within a range of up to 200 kilobases (kb), generating linked-reads...

The recent development of single-cell and single-nucleus RNA sequencing has highlighted the extraordinary diversity of dorsal root ganglia neurons. However, the few available genetic tools limit our understanding of the functional significance of this heterogeneity. We generated a new mouse line expressing the flippase recombinase from the scn10a locus. By crossing Nav 1.8Ires-FLPo mice with the AdvillinCre and RC::FL-hM3Dq mouse lines in an intersectional genetics approach, we were able to obtain somatodendritic expression of hM3Dq-mCherry selectively in the Nav 1...

Adipocytes normally accumulate in the epicardial and pericardial layers around the human heart, but their infiltration into the myocardium can be proarrhythmic. METHODS AND RESULTS: Human adipose derived stem/stromal cells and human induced pluripotent stem cells (hiPSC) were differentiated, respectively into predominantly white fat-like adipocytes (hAdip) and ventricular cardiomyocytes (CMs). Adipocytes cultured in CM maintenance medium (CM medium) maintained their morphology, continued to express adipogenic markers, and retained clusters of intracellular lipid droplets...

OBJECTIVE: This study explored the potentially modifiable factors for depression and major depressive disorder (MDD) from the MR-Base database and further evaluated the associations between drug targets with MDD. METHODS: We analyzed two-sample of Mendelian randomization (2SMR) using genetic variant depression ( n = 113,154) and MDD ( n = 208,811) from Genome-Wide Association Studies (GWAS). Separate calculations were performed with modifiable risk factors from MR-Base for 1,001 genomes...

Despite the recognized importance of the spinal cord in sensory processing, motor behaviors, and neural diseases, the underlying organization of neuronal clusters and their spatial location remain elusive. Recently, several studies have attempted to define the neuronal types and functional heterogeneity in the spinal cord using single-cell or single-nucleus RNA sequencing in animal models or developing humans. However, molecular evidence of cellular heterogeneity in the adult human spinal cord is limited. Here, we classified spinal cord neurons into 21 subclusters and determined their distribution from nine human donors using single-nucleus RNA sequencing and spatial transcriptomics...

BACKGROUND: Silent inflammatory bowel disease (IBD) is a condition in which individuals with the active disease experience minor to no pain. Voltage-gated Na+ (NaV ) channels expressed in sensory neurons play a major role in pain perception. Previously, we reported that a NaV 1.8 genetic polymorphism (A1073V, rs6795970) was more common in a cohort of silent IBD patients. The expression of this variant (1073V) in rat sympathetic neurons activated at more depolarized potentials when compared to the more common variant (1073A)...

Pain is a widespread non-motor symptom that presents significant treatment challenges in patients with Parkinson's disease (PD). Safinamide, a new drug recently introduced for PD treatment, has demonstrated analgesic effects on pain in PD patients, though the underlying mechanisms remain unclear. To investigate the analgesic and anti-PD effect of safinamide, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model was used, and rasagiline as positive control on motor symptoms. Notably, only safinamide alleviated hyperalgesia in MPTP mice...

The voltage-gated sodium channel NaV 1.8 is prominently expressed in the soma and axons of small-caliber sensory neurons, and pathogenic variants of the corresponding gene SCN10A are associated with peripheral pain and autonomic dysfunction. While most disease-associated SCN10A variants confer gain-of-function properties to NaV 1.8, resulting in hyperexcitability of sensory neurons, a few affect afferent excitability through a loss-of-function mechanism. Using whole-exome sequencing, we here identify a rare heterozygous SCN10A missense variant resulting in alteration p...

Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study...

Clinical studies suggest low testosterone levels are associated with cardiac arrhythmias, especially in later life. We investigated whether chronic exposure to low circulating testosterone promoted maladaptive electrical remodeling in ventricular myocytes from aging male mice and determined the role of late inward sodium current (INa-L ) in this remodeling. C57BL/6 mice had a gonadectomy (GDX) or sham surgery (1-month) and were aged to 22-28-months. Ventricular myocytes were isolated; transmembrane voltage and currents were recorded (37°C)...

In heart failure and atrial fibrillation, a persistent Na+ current (INaL ) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that NaV 1.8 contributes to arrhythmogenesis by inducing a INaL . Genome-wide association studies indicate that mutations in the SCN10A gene (NaV 1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these NaV 1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion...

Nav1.8, a tetrodotoxin-resistant voltage-gated sodium channels (VGSCs) subtype encoded by SCN10A, which plays an important role in the production and transmission of peripheral neuropathic pain signals. Studies have shown that VGSCs may be key targets of MicroRNAs (miRNAs) in the regulation of neuropathic pain. In our study, bioinformatics analysis showed that the targeting relationship between miR-3584-5p and Nav1.8 was the most closely. The purpose of this study was to investigate the roles of miR-3584-5p and Nav1...

BACKGROUND: Artificial intelligence (AI) models applied to 12-lead ECG waveforms can predict atrial fibrillation (AF), a heritable and morbid arrhythmia. However, the factors forming the basis of risk predictions from AI models are usually not well understood. We hypothesized that there might be a genetic basis for an AI algorithm for predicting the 5-year risk of new-onset AF using 12-lead ECGs (ECG-AI)-based risk estimates. METHODS: We applied a validated ECG-AI model for predicting incident AF to ECGs from 39 986 UK Biobank participants without AF...

OBJECTIVE: To utilize whole exome or genome sequencing and the scientific literature for identifying candidate genes for cyclic vomiting syndrome (CVS), an idiopathic migraine variant with paroxysmal nausea and vomiting. METHODS: A retrospective chart review of 80 unrelated participants, ascertained by a quaternary care CVS specialist, was conducted. Genes associated with paroxysmal symptoms were identified querying the literature for genes associated with dominant cases of intermittent vomiting or both discomfort and disability; among which the raw genetic sequence was reviewed...

INTRODUCTION: The present study aimed to investigate the possible association between the single-nucleotide polymorphisms (SNPs) in the SCN9A, SCN10A, SCN11A, OPRM1, and COMT genes and the success rate of pulpal anesthesia after inferior alveolar nerve block (IANB). METHODS: A total of 70 patients (45 females and 25 males) presenting mandibular molar teeth with symptomatic irreversible pulpitis were included. Saliva samples were collected from the participants before the application of IANB...

Neuropathic pain is a frequent feature of diabetic peripheral neuropathy (DPN) and small fiber neuropathy (SFN). Resolving the genetic architecture of these painful neuropathies will lead to better disease management strategies, counselling and intervention. Our aims were to profile ten sodium channel genes (SCG) expressed in a nociceptive pathway in painful and painless DPN and painful and painless SFN patients, and to provide a perspective for clinicians who assess patients with painful peripheral neuropathy...

We illustrate use of induced pluripotent stem cells (iPSCs) as platforms for investigating cardiomyocyte phenotypes in a human family pedigree exemplified by novel heterozygous RYR2-A1855D and SCN10A-Q1362H variants occurring alone and in combination. The proband, a four-month-old boy, presented with polymorphic ventricular tachycardia. Genetic tests revealed double novel heterozygous RYR2-A1855D and SCN10A-Q1362H variants inherited from his father (F) and mother (M), respectively. His father showed ventricular premature beats; his mother was asymptomatic...

In the human genome, heterozygous sites are genomic positions with different alleles inherited from each parent. On average, there is a heterozygous site every 1-2 kilobases (kb). Resolving whether two alleles in neighboring heterozygous positions are physically linked-that is, phased-is possible with a short-read sequencer if the sequencing library captures long-range information. TELL-Seq is a library preparation method based on millions of barcoded micro-sized beads that enables instrument-free phasing of a whole human genome in a single PCR tube...

Despite the high prevalence of chronic pain as a disease in our society, there is a lack of effective treatment options for patients living with this condition. Gene therapies using recombinant AAVs are a direct method to selectively express genes of interest in target cells with the potential of, in the case of nociceptors, reducing neuronal firing in pain conditions. We designed a recombinant AAV vector expressing cargos whose expression was driven by a portion of the SCN10A (NaV 1.8) promoter, which is predominantly active in nociceptors...

BACKGROUND: The Worm Study, ascertained from a multigeneration pedigree segregating a single amino acid deletion in SCN5A (c.4850_4852delTCT, p.(Phe1617del), rs749697698), is characterized by substantial phenotypic heterogeneity and overlap of sudden cardiac death, long-QT syndrome, cardiac conduction disease, Brugada syndrome, and isorhythmic atrioventricular dissociation. Linkage analysis for a synthetic trait derived from these phenotypes identified a single peak (logarithm of the odds [LOD] = 4...