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Background: Postoperative pain intensity is influenced by various factors, including genetic variations. The SCN10A gene encodes the Nav1.8 sodium channel protein, which is crucial for pain signal transmission in peripheral sensory neurons. Objectives: This study aims to investigate the relationship between genetic mutations in the SCN10A gene (rs6795970) and postoperative analgesic effects following gynecological laparoscopic surgery. Methods: Two hundred female patients undergoing gynecological laparoscopic surgery under general anesthesia were included. pain sensitivity was evaluated using the catastrophizing scale and pain sensitivity questionnaire (PSQ). Patients received patient-controlled intravenous analgesia with sufentanil and dexmedetomidine for 48 h post-surgery. Postoperative pain indicators, such as visual analog scale (VAS) scores, Ramsay scores, and side effects were recorded. SCN10A rs6795970 mutations were identified using MassARRAY SNP typing technology, and patients were categoried into homozygous mutant (AA), wild type (GG), and heterozygous mutation (GA) groups for analysis. Results: Patients in the AA group had higher scores on the pain Catastrophizing Scale, PSQ-total, PSQ-minor, and PSQ-moderate compared to GA and GG groups (P < 0.05). VAS scores at 4, 6, and 12 h post-operation were higher in the AA group than the GG group (P < 0.05). Ramsay scores were lower in AA patients at 2 and 4 h post-operation compared to GA and GG groups (P < 0.05). The AA group exhibited more self-control analgesic pump compressions within the first 24 h post-surgery, quicker depletion of analgesics in the pump, and lower patient satisfaction with pain relief compared to GA and GG groups (P < 0.05). Conclusions: Female patients with homozygous SCN10A mutations may experience higher preoperative pain scores and increased sensitivity to postoperative pain following gynecological laparoscopic surgery with intravenous patient-controlled analgesia. Trial registration: www.chictr.org.cn, registration number: ChiCTR2200062425. [ABSTRACT FROM AUTHOR]

Abstract Background Postoperative pain intensity is influenced by various factors, including genetic variations. The SCN10A gene encodes the Nav1.8 sodium channel protein, which is crucial for pain signal transmission in peripheral sensory neurons. Objectives This study aims to investigate the relationship between genetic mutations in the SCN10A gene (rs6795970) and postoperative analgesic effects following gynecological laparoscopic surgery. Methods Two hundred female patients undergoing gynecological laparoscopic surgery under general anesthesia were included. pain sensitivity was evaluated using the catastrophizing scale and pain sensitivity questionnaire (PSQ). Patients received patient-controlled intravenous analgesia with sufentanil and dexmedetomidine for 48 h post-surgery. Postoperative pain indicators, such as visual analog scale (VAS) scores, Ramsay scores, and side effects were recorded. SCN10A rs6795970 mutations were identified using MassARRAY SNP typing technology, and patients were categoried into homozygous mutant (AA), wild type (GG), and heterozygous mutation (GA) groups for analysis. Results Patients in the AA group had higher scores on the pain Catastrophizing Scale, PSQ-total, PSQ-minor, and PSQ-moderate compared to GA and GG groups (P

The sodium channel NaV1.8, encoded by the SCN10A gene, has recently emerged as a potential regulator of cardiac electrophysiology. We have previously shown that NaV1.8 contributes to arrhythmogenesis by inducing a persistent Na+ current (late Na+ current, INaL) in human atrial and ventricular cardiomyocytes (CM). We now aim to further investigate the contribution of NaV1.8 to human ventricular arrhythmogenesis at the CM-specific level using pharmacological inhibition as well as a genetic knockout (KO) of SCN10A in induced pluripotent stem cell CM (iPSC-CM). In functional voltage-clamp experiments, we demonstrate that INaL was significantly reduced in ventricular SCN10A-KO iPSC-CM and in control CM after a specific pharmacological inhibition of NaV1.8. In contrast, we did not find any effects on ventricular APD90. The frequency of spontaneous sarcoplasmic reticulum Ca2+ sparks and waves were reduced in SCN10A-KO iPSC-CM and control cells following the pharmacological inhibition of NaV1.8. We further analyzed potential triggers of arrhythmias and found reduced delayed afterdepolarizations (DAD) in SCN10A-KO iPSC-CM and after the specific inhibition of NaV1.8 in control cells. In conclusion, we show that NaV1.8-induced INaL primarily impacts arrhythmogenesis at a subcellular level, with minimal effects on systolic cellular Ca2+ release. The inhibition or knockout of NaV1.8 diminishes proarrhythmic triggers in ventricular CM. In conjunction with our previously published results, this work confirms NaV1.8 as a proarrhythmic target that may be useful in an anti-arrhythmic therapeutic strategy. [ABSTRACT FROM AUTHOR]

The voltage-gated sodium channel NaV1.8 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 NaV1.8, 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.V1287I in NaV1.8 in a patient with a 15-year history of progressively worsening temperature dysregulation in the distal extremities, particularly in the feet. Further symptoms include increasingly intensifying tingling and numbness in the fingers and increased sweating. To assess the impact of p.V1287I on channel function, we performed voltage-clamp recordings demonstrating that the alteration confers loss- and gain-of-function characteristics to NaV1.8 characterized by a right-shifted voltage dependence of channel activation and inactivation. Current-clamp recordings from transfected mouse dorsal root ganglion neurons further revealed that NaV1.8-V1287I channels broaden the action potentials of sensory neurons and increase their firing rates in response to depolarizing current stimulations, indicating a gain-of-function mechanism of the variant at the cellular level in a heterozygous setting. The data support the hypothesis that the properties of NaV1.8 p.V1287I are causative for the patient's symptoms and that nonpainful peripheral paresthesias should be considered part of the clinical spectrum of NaV1.8-associated disorders. [ABSTRACT FROM AUTHOR]

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. Molecular biological characterizations demonstrated greater TNNT2 messenger RNA (mRNA) expression in the iPSCs-induced cardiomyocytes (iPS-CMs) than in the iPSCs. Cardiac troponin Ts became progressively organized but cytoplasmic RYR2 and SCN10A aggregations occurred in the iPS-CMs. Proband-specific iPS-CMs showed decreased RYR2 and SCN10A mRNA expression. The RYR2-A1855D variant resulted in premature spontaneous sarcoplasmic reticular Ca2+ transients, Ca2+ oscillations and increased action potential durations. SCN10A-Q1362H did not confer any specific phenotype. However, the combined heterozygous RYR2-A1855D and SCN10A-Q1362H variants in the proband iPS-CMs resulted in accentuated Ca2+ homeostasis disorders, action potential prolongation and susceptibility to early afterdepolarizations at high stimulus frequencies. These findings attribute the clinical phenotype in the proband to effects of the heterozygous RYR2 variant exacerbated by heterozygous SCN10A modification. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'. [ABSTRACT FROM AUTHOR]

Objective To investigate the association between sinus tachycardia and SCN10A gene. Methods A case of patient with inappropriate sinus tachycardia and SCN10A gene mutation was analyzed. Using the keywords of “sinus tachycardia”and“SCN10A”, relavant literatures were searched from PubMed, GeenMedical, CNKI, WangFang and Vip databases. Literatures of SCN10A-related heart disease were collected and analyzed. Results A 12-year-old boy was admitted to the hospital with “dizziness, weakness of limbs with pale after strenuous exercise for 5 years, and increased heart rate for 2 years”. The father, father’s sister and the boy’s sister had a medical history of “sinus tachycardia” in the family. The electrocardiogram showed sinus tachycardia （heart rate 120-130 bpm）. Whole exon sequencing revealed that the patient carried SCN10A and CACNA1S gene mutation. His sister had the same gene mutation. Five literatures of SCN10A-related heart diseases were collected, and the results showed that SCN10A gene was closely related to cardiac conduction system function and various arrhythmias, including atrial fibrillation, Brugada syndrome, heart failure and myocardial hypertrophy, etc. Conclusion In this study, it is believed that SCN10A gene mutation is closely related to inappropriate sinus tachycardia, which may provide new ideas and new directions for the treatment of inappropriate sinus tachycardia, further studies are needed to verify it.

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). 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. A standard IANB was performed with 1.8 mL 4% articaine with 1:100,000 epinephrine. Endodontic treatment was initiated 15 minutes after injection, and the patients were asked to report their pain level during the procedure on a 170-mm Heft-Parker visual analog scale. If the patient recorded a pain level of lower than 54 on the visual analog scale (no pain or mild pain), the anesthesia was considered successful. The DNA isolation and genotyping were performed, and the association between rs4286289, rs6746030, rs6795970, rs6801957, rs11709492, rs1799971, rs1799973, rs4680, rs6269, rs4633, and rs740603 SNPs and the success rate of anesthesia was investigated. The anesthesia success rate was significantly lower for the GG genotypes (45%) than the GA and AA genotypes (90%) for rs6795970 in the SCN10A gene. Additionally, the A allele for rs6795970 and the T allele for rs6801957 in the SCN10A gene were significantly associated with higher anesthesia success rates. SNPs in the SCN10A gene affect the success rate of pulpal anesthesia after IANB. [ABSTRACT FROM AUTHOR]

Congenital long QT syndrome (LQTS) is a type of cardiac ion channelopathy that increases the susceptibility of the affected individuals to spontaneous ventricular tachycardia/fibrillation or even sudden cardiac death. More than 17 subtypes have been identified. This was a systematic review of the published case series or reports on the clinical characteristics, genetic basis, and patient outcomes from Hong Kong with rare genetic variants of LQTS which fall outside the traditional LQTS classification system. PubMed and Zenodo were searched from the corresponding inception until January 15, 2022. Twenty-four studies were identified. Of these, one article met the inclusion criteria. The article included a case series of six patients from a cohort with 134 patients. They had either asymptomatic LQTS with HCN4 mutations (n = 1, c.1471G>A, QTc: 420 ms with prolonged QTc of 670 ms during the recovery phase of treadmill test), RYR2 (n = 1, c.7060G>A, QTc: 480 ms) or SCN10A (n = 2, c.3542C>T, QTc: 439 ms-480 ms), or LQTS with multiorgan syndromes with GATA3 mutations (n = 1, c. 815C>T, Barakat syndrome: Sensorineural deafness, hypoparathyroidism, and renal disease, QTc: 450-489 ms), or SLC6A8 (n = 1, c.691_693del; X-linked creatine transporter deficiency, with c.6065A>G mutation in AKAP9, known modifier of LQTS; QTc: 485 ms). In addition, rare genetic variants in non-LQTS causative genes were identified. Future studies should be conducted to compare the variants and investigate their functional consequences. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association between postoperative pain intensity and single nucleotide polymorphisms (SNPs) in the SCN9A, SCN10A, and SCN11A genes. Methods: Ninety-five patients were included in the study. All the participants recorded their preoperative percussion and preoperative pain levels on a visual analog scale (VAS) before root canal treatment. After the treatment, a form including the VAS was given to the patients to record their pain values and use of analgesics on the 1st, 2nd, 3rd, and 7th days after the treatment. DNA isolation and genotyping were performed and the association between polymorphisms and postoperative pain level was investigated. Results: The AA genotype at the SNP rs6746030 and the CC genotype at rs4286289 of the SCN9A gene were significantly associated with higher postoperative pain levels. The CC genotype at SNP rs6801957 in the SCN10A gene was significantly associated with less postoperative pain. Conclusion: The rs6746030 and rs4286289 SNPs in the SCN9A gene and rs6801957 in the SCN10A gene were associated with pain level after endodontic treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Sodium channels located in the dorsal root ganglion, particularly Nav1.7 and Nav1.8, encoded by SCN9A and SCN10A, respectively, act as molecular gatekeepers for pain detection. Our aim was to determine the association between TIPN and SCN9A and SCN10A polymorphisms. Methods Three single nucleotide polymorphisms (SNPs) in SCN9A and two in SCN10A were investigated using whole-genome genotyping data from 186 Japanese breast or ovarian cancer patients classified into two groups as follows: cases that developed taxane-induced grade 2–3 neuropathy (N = 108) and controls (N = 78) with grade 0–1 neuropathy. Multiple logistic regression analyses were conducted to evaluate associations between TIPN and SNP genotypes. Results SCN9A-rs13017637 was a significant predictor of grade 2 or higher TIPN (odds ratio (OR) = 3.463; P = 0.0050) after correction for multiple comparisons, and precision was improved when only breast cancer patients were included (OR 5.053, P = 0.0029). Moreover, rs13017637 was a significant predictor of grade 2 or higher TIPN 1 year after treatment (OR 3.906, P = 0.037), indicating its contribution to TIPN duration. Conclusion SCN9A rs13017637 was associated with the severity and duration of TIPN. These findings are highly exploratory and require replication and validation prior to any consideration of clinical use.

The voltage-gated sodium channel NAV1.8 is expressed in primary nociceptive neurons and is involved in pain transmission. Mutations in the SCN10A gene (encoding NAV1.8 channel) have been identified in patients with idiopathic painful small fiber neuropathy (SFN) including the SCN10AG1662S gain-of-function mutation. However, the role of this mutation in pain sensation remains unknown. We have generated the first mouse model for the G1662S mutation by using homologous recombination in embryonic stem cells. The corresponding Scn10aG1663S mouse line has been analyzed for Scn10a expression, intraepidermal nerve fiber density (IENFD), and nociception using behavioral tests for thermal and mechanical sensitivity. The Scn10aG1663S mutants had a similar Scn10a expression level in dorsal root ganglia (DRG) to their wild-type littermates and showed normal IENFD in hindpaw skin. Mutant mice were more sensitive to touch than wild types in the von Frey test. In addition, sexual dimorphism was observed for several pain tests, pointing to the relevance of performing the phenotypical assessment in both sexes. Female homozygous mutants tended to be more sensitive to cooling stimuli in the acetone test. For heat sensitivity, male homozygous mutants showed shorter latencies to radiant heat in the Hargreaves test while homozygous females had longer latencies in the tail flick test. In addition, mutant males displayed a shorter reaction latency on the 54°C hot plate. Collectively, Scn10aG1663S mutant mice show a moderate but consistent increased sensitivity in behavioral tests of nociception. This altered nociception found in Scn10aG1663S mice demonstrates that the corresponding G1662 mutation of SCN10A found in SFN patients with pain contributes to their pain symptoms. [ABSTRACT FROM AUTHOR]

The voltage-gated sodium channel NAV1.8 is expressed in primary nociceptive neurons and is involved in pain transmission. Mutations in the SCN10A gene (encoding NAV1.8 channel) have been identified in patients with idiopathic painful small fiber neuropathy (SFN) including the SCN10AG1662S gain-of-function mutation. However, the role of this mutation in pain sensation remains unknown. We have generated the first mouse model for the G1662S mutation by using homologous recombination in embryonic stem cells. The corresponding Scn10aG1663S mouse line has been analyzed for Scn10a expression, intraepidermal nerve fiber density (IENFD), and nociception using behavioral tests for thermal and mechanical sensitivity. The Scn10aG1663S mutants had a similar Scn10a expression level in dorsal root ganglia (DRG) to their wild-type littermates and showed normal IENFD in hindpaw skin. Mutant mice were more sensitive to touch than wild types in the von Frey test. In addition, sexual dimorphism was observed for several pain tests, pointing to the relevance of performing the phenotypical assessment in both sexes. Female homozygous mutants tended to be more sensitive to cooling stimuli in the acetone test. For heat sensitivity, male homozygous mutants showed shorter latencies to radiant heat in the Hargreaves test while homozygous females had longer latencies in the tail flick test. In addition, mutant males displayed a shorter reaction latency on the 54°C hot plate. Collectively, Scn10aG1663S mutant mice show a moderate but consistent increased sensitivity in behavioral tests of nociception. This altered nociception found in Scn10aG1663S mice demonstrates that the corresponding G1662 mutation of SCN10A found in SFN patients with pain contributes to their pain symptoms.

SCN10A/NaV1.8 may be associated with a lower risk of ventricular fibrillation in the setting of acute myocardial infarction (AMI), but if and by which mechanism NaV1.8 impacts on ventricular electrophysiology is still a matter of debate. The purpose of this study was to elucidate the contribution of NaV1.8 in ganglionated plexi (GP) to ventricular arrhythmias in the AMI model. Twenty beagles were randomized to either the A-803467 group (n = 10) or the control group (n = 10). NaV1.8 blocker (A-803467, 1 μmol/0.5 mL per GP) or DMSO (0.5 mL per GP) was injected into four major GPs. Ventricular effective refractory period, APD90, ventricular fibrillation threshold, and the incidence of ventricular arrhythmias were measured 1 h after left anterior descending coronary artery occlusion. A-803467 significantly shortened ventricular effective refractory period, APD90, and ventricular fibrillation threshold compared to control. In the A-803467 group, the incidence of ventricular arrhythmias was significantly higher compared to control. A-803467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP, suggesting that A-803467 could inhibit GP activity. SCN10A/NaV1.8 was readily detected in GPs, but was not validated in ventricles by quantitative RT-PCR, western blot and immunohistochemistry. While SCN10A/NaV1.8 is detectible in canine GPs but not in ventricles, blockade of NaV1.8 in GP increases the incidence of ventricular arrhythmias in AMI hearts. Our study shows for the first time an influence of SCN10A/NaV1.8 on the regulation of ventricular arrhythmogenesis via modulating GP activity in the AMI model.

Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A , SCN10A , and SCN9A , which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A , SCN10A , and SCN9A . In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A , SCN10A , and SCN9A , respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.

Background: Sodium channels located in the dorsal root ganglion, particularly Nav1.7 and Nav1.8, encoded by SCN9A and SCN10A, respectively, act as molecular gatekeepers for pain detection. Our aim was to determine the association between TIPN and SCN9A and SCN10A polymorphisms.Methods: Three single nucleotide polymorphisms (SNPs) in SCN9A and two in SCN10A were investigated using whole-genome genotyping data from 186 Japanese breast or ovarian cancer patients classified into two groups as follows: cases that developed taxane-induced grade 2-3 neuropathy (N = 108) and controls (N = 78) with grade 0-1 neuropathy. Multiple logistic regression analyses were conducted to evaluate associations between TIPN and SNP genotypes.Results: SCN9A-rs13017637 was a significant predictor of grade 2 or higher TIPN (odds ratio (OR) = 3.463; P = 0.0050) after correction for multiple comparisons, and precision was improved when only breast cancer patients were included (OR 5.053, P = 0.0029). Moreover, rs13017637 was a significant predictor of grade 2 or higher TIPN 1 year after treatment (OR 3.906, P = 0.037), indicating its contribution to TIPN duration.Conclusion: SCN9A rs13017637 was associated with the severity and duration of TIPN. These findings are highly exploratory and require replication and validation prior to any consideration of clinical use. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) caused by nerve injury or dysfunction is one of the most challenging neurological diseases. In‐depth study of disease signatures contributes to the development of novel target treatment for NP. In this study, we analyzed expression profiles of qualified NP datasets (GSE24982 and GSE63442) deposited at Gene Expression Omnibus database by systematic bioinformatics approaches. We analyzed the differentially expressed genes of high and low pain compared with normal control group, and between spinal nerve ligation (SNL) injury model and sham‐operation group. A total of 1,243 upregulated and 1,533 downregulated genes were identified in GSE24982, 380 upregulated and 355 downregulated genes were identified in GSE63442. By comparing low‐pain samples with the corresponding sham‐operation group, we identified 457 upregulated and 409 downregulated genes. Overlapping genes were screened out and signaling pathway and expression regulation model analyses were performed. SCN10A and SST were identified as biomarkers for NP. In conclusion, our study showed the expression pattern of gene about NP. These identified biomarkers could serve as potential therapeutic targets for treating NP. [ABSTRACT FROM AUTHOR]

Aims: The Brugada syndrome (BrS) is an inherited disease associated with an increased risk of sudden cardiac death. Often, the genetic cause remains undetected. Perhaps due at least in part because the NaV1.8 protein is expressed more in both the central and peripheral nervous systems than in the heart, the SCN10A gene is not included in diagnostic arrhythmia/sudden death panels in the vast majority of cardiogenetics centres.Methods and Results: Clinical characteristics were assessed in patients harboring either SCN5A or novel SCN10A variants. Genetic testing was performed using Next Generation Sequencing on genomic DNA. Clinical characteristics, including the arrhythmogenic substrate, in BrS patients harboring novel SCN10A variants and SCN5A variants are comparable. Clinical characteristics, including gender, age, personal history of cardiac arrest/syncope, spontaneous BrS electrocardiogram pattern, family history of sudden death, and arrhythmic substrate are not significantly different between probands harboring SCN10A or SCN5A variants.Conclusion: Future studies are warranted to further characterize the role of these specific SCN10A variants. [ABSTRACT FROM AUTHOR]

Aims: Brugada syndrome (BrS) is associated with a pronounced risk to develop sudden cardiac death (SCD). Up to 21% of patients are related to mutations in SCN5A. Studies identified SCN10A as a contributor of BrS. However, the investigation of the human cellular phenotype of BrS in the presence of SCN10A mutations remains lacking. The objective of this study was to establish a cellular model of BrS in presence of SCN10A mutations using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).Methods and Results: Dermal fibroblasts obtained from a BrS patient suffering from SCD harbouring the SCN10A double variants (c.3803G>A and c.3749G>A) and three independent healthy control subjects were reprogrammed to hiPSCs. Human-induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs).The hiPSC-CMs from the BrS patient showed a significantly reduced peak sodium channel current (INa) and a significantly reduced ATX II (sea anemone toxin, an enhancer of late INa) sensitive as well as A-887826 (a blocker of SCN10A channel) sensitive late sodium channel current (INa) when compared with the healthy control hiPSC-CMs, indicating loss-of-function of sodium channels. Consistent with reduced INa the action potential amplitude and upstroke velocity (Vmax) were significantly reduced, which may contribute to arrhythmogenesis of BrS. Moreover, Ajmaline effects on action potentials were stronger in BrS-hiPSC-CMs than in healthy control cells. This is in agreement with the higher susceptibility of patients to sodium channel blocking drugs in unmasking BrS.Conclusion: Patient-specific hiPSC-CMs are able to recapitulate single-cell phenotype features of BrS with SCN10A mutations and may provide novel opportunities to further elucidate the cellular disease mechanism. [ABSTRACT FROM AUTHOR]

Background: Multiple genome-wide association studies (GWAS) and targeted gene sequencing have identified common variants in SCN10A in cases of PR and QRS duration abnormalities, atrial fibrillation and Brugada syndrome. The New York City Office of Chief Medical Examiner has now also identified five SCN10A variants of uncertain significance in six separate cases within a cohort of 330 sudden unexplained death events. The gene product of SCN10A is the Nav1.8 sodium channel. The purpose of this study was to characterize effects of these variants on Nav1.8 channel function to provide better information for the reclassification of these variants.Methods and Results: Patch clamp studies were performed to assess effects of the variants on whole-cell Nav1.8 currents. We also performed RNA-seq analysis and immunofluorescence confocal microcopy to determine Nav1.8 expression in heart. We show that four of the five rare 'variants of unknown significance' (L388M, L867F, P1102S and V1518I) are associated with altered functional phenotypes. The R756W variant behaved similar to wild-type under our experimental conditions. We failed to detect Nav1.8 protein expression in immunofluorescence microscopy in rat heart. Furthermore, RNA-seq analysis failed to detect full-length SCN10A mRNA transcripts in human ventricle or mouse specialized cardiac conduction system, suggesting that the effect of Nav1.8 on cardiac function is likely to be extra-cardiac in origin.Conclusions: We have demonstrated that four of five SCN10A variants of uncertain significance, identified in unexplained death, have deleterious effects on channel function. These data extend the genetic testing of SUD cases, but significantly more clinical evidence is needed to satisfy the criteria needed to associate these variants with the onset of SUD. [ABSTRACT FROM AUTHOR]

Background: Hypoalgesic inflammatory bowel disease (IBD), a condition in which patients with active disease do not perceive and/or report abdominal pain, is associated with serious complications and there is a lack of cost-effective, reliable diagnostic methods to identify “at-risk” patients. The voltage-gated sodium channels (VGSC's), Nav1.7, Nav1.8, and Nav1.9, are preferentially expressed on nociceptive neurons, and have been implicated in visceral inflammatory pain. At least 29 VGSC single nucleotide polymorphisms (SNPs) have been implicated in chronic somatic pain syndromes, but little is known about their role in human visceral sensation. We hypothesized that disruptive VGSC polymorphisms result in anti-nociceptive behavior in IBD.Methods and Findings: We performed targeted exome sequencing and/or TaqMan genotyping to evaluate the Nav1.7, Nav1.8, and Nav1.9 genes (SCN9A, SCN10A and SCN11A) in 121 IBD patients (including 41 “hypoalgesic” IBD patients) and 86 healthy controls. Allelic and genotypic frequencies of polymorphisms were compared among study groups who had undergone characterization of intestinal inflammatory status and abdominal pain experience. Forty-nine total exonic SNPs were identified. The allelic frequency of only one non-synonymous SNP (rs6795970 [SCN10A]) approached significance in hypoalgesic IBD patients when compared to other IBD patients (p = 0.096, Fisher's exact test). Hypoalgesic IBD patients were more likely to be homozygous for this polymorphism (46 vs. 22%, p = 0.01, Fisher's exact test).Conclusions: This is the first human study to demonstrate a link between a genetic variant of SCN10A and abdominal pain perception in IBD. These findings provide key insights into visceral nociceptive physiology and new diagnostic and therapeutic targets to consider in IBD and other gastrointestinal conditions associated with chronic abdominal pain. Further studies are required to elucidate the precise pathophysiological impact of the rs6795970 polymorphism on human gastrointestinal nociception.

Abstract Prior work demonstrated that a splice variant of SCN5A , a voltage-gated sodium channel gene, acts as a cytoplasmic sensor for viral dsRNA in human macrophages. Expression of this channel also polarizes macrophages to an anti-inflammatory phenotype in vitro and in vivo. Here we utilized global expression analysis of splice variants to identify novel channel-dependent signaling mechanisms. Pharmacological activation of voltage-gated sodium channels in human macrophages, but not treatment with cytoplasmic poly I:C, was associated with splicing of a retained intron in transcripts of PPP1R10 , a regulator of phosphatase activity and DNA repair. Microarray analysis also demonstrated expression of a novel sodium channel splice variant, human macrophage SCN10A , that contains a similar exon deletion as SCN5A. SCN10A localizes to cytoplasmic and nuclear vesicles in human macrophages. Simultaneous expression of human macrophage SCN5A and SCN10A was required to decrease expression of the retained intron and increase protein expression of PPP1R10. Channel activation also increased protein expression of the splicing factor EFTUD2 , and knockdown of EFTUD2 prevented channel dependent splicing of the retained PPP1R10 intron. Knockdown of the SCN5A and SCN10A variants in human macrophages reduced the severity of dsDNA breaks induced by treatment with bleomycin and type 1 interferon. These results suggested that human macrophage SCN5A and SCN10A variants mediate an innate immune signaling pathway that limits DNA damage through increased expression of PPP1R10. The functional significance of this pathway is that it may prevent cytotoxicity during inflammatory responses. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The voltage gated sodium channel Na V 1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole Na V 1.8 blockers. Subsequent optimization allowed the identification of compound 9 , PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile. [ABSTRACT FROM AUTHOR]

Introduction: Sudden cardiac death is an important cause of mortality in the general population. It represents an important challenge for clinicians, often being the only symptom of a broad spectrum of cardiac pathologies and inherited heart conditions. Early repolarization syndrome and Brugada syndrome are part of the wider "J-wave" syndrome, which may also include the short QT syndrome as a third factor of an ionic channel imbalance in the arrhythmogenic landscape.Case Presentation: We describe the case of a woman struck down by sudden cardiac death, with short QT and early repolarization, in which we found an extremely rare and putatively pathogenic heterozygous variant in the SCN10A gene. Variants involving SCN10A, which encodes a voltage-gated sodium channel, were already associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder, thereby influencing the cardiac physiology and predisposing to arrhythmia.Conclusion: We underline the role of genetic predisposition to sudden cardiac death and, for the first time, suggest a possible environmental effect, such as a pharmacological therapy in the setting of sudden death, with the purpose to increase awareness in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Long QT syndrome (LQT) is a pro‐arrhythmogenic condition with life‐threatening complications. Fifteen genes have been associated with congenital LQT, however, the genetic causes remain unknown in more than 20% of cases. Materials and Methods: Eighteen patients with history of palpitations, pre‐syncope, syncope and prolonged QT were referred to the Yale Cardiovascular Genetics Program. All subjects underwent whole‐exome sequencing (WES) followed by confirmatory Sanger sequencing. Mutation burden analysis was carried out using WES data from 16 subjects with no identifiable cause of LQT. Results: Deleterious and novel SCN10A mutations were identified in 3 of the 16 patients (19%) with idiopathic LQT. These included 2 frameshifts and 1 missense variants (p.G810fs, p.R1259Q, and p.P1877fs). Further analysis identified 2 damaging SCN10A mutations with allele frequencies of approximately 0.2% (p.R14L and p.R1268Q) in 2 independent cases. None of the SCN10A mutation carriers had mutations in known arrhythmia genes. Damaging SCN10A mutations (p.R209H and p.R485C) were also identified in the 2 subjects on QT prolonging medications. Conclusion: Our findings implicate SCN10A in LQT. The presence of frameshift mutations suggests loss‐of‐function as the underlying disease mechanism. The common association with atrial fibrillation suggests a unique mechanism of disease for this LQT gene. [ABSTRACT FROM AUTHOR]

Sudden unexpected death in infants (SUDI) is a devastating event for a family, and unfortunately occurs relatively frequently in South Africa. These cases are referred for a forensic post-mortem investigation to establish the cause of death; however, despite thorough analyses, some cases remain undetermined. Internationally, a molecular autopsy has assisted in resolving these types of cases by revealing genetic variants which contributed to the demise. Motivated by lack of local research in this field, a study was launched at the University of Cape Town (South Africa) in 2015 to explore the use of molecular autopsies in the medico-legal investigation of local SUDI cases. An ethical framework was established and used to prospectively recruit SUDI cases from one of the busiest forensic facilities: Salt River Mortuary. A next generation sequencing approach was used to assess 43 genes previously associated with cardiac arrhythmias. In a particular infant, a putative pathogenic variant was identified (rs750771811 T/T) in the SCN10A gene. The variant is rare, but was homozygous in this infant, and appears to be the first time it has been observed in a SUDI victim. Previous functional studies on the amino-acid residue suggested that this variant may reduce SCN5A activity, which has been linked to Brugada syndrome. A genetic counselling session was arranged with the parents; a full family history was obtained, which revealed that the parents had a previous miscarriage and had recently had a second SUDI. The parents have subsequently been enrolled in the study for genetic screening and have been referred for electrocardiogram assessments. The findings highlight a new possible candidate variant to assess in SUDI cases, and also demonstrate the value of molecular autopsies to families. [ABSTRACT FROM AUTHOR]

BackgroundGanglionated plexus have been developed as additional ablation targets to improve the outcome of atrial fibrillation (AF) besides pulmonary vein isolation. Recent studies implicated an intimate relationship between neuronal sodium channel Nav1.8 (encoded by SCN10A) and AF. The underlying mechanism between Nav1.8 and AF remains unclear. This study aimed to determine the role of Nav1.8 in cardiac electrophysiology in an acute AF model and explore possible therapeutic targets. Methods and ResultsImmunohistochemical study was used on canine cardiac ganglionated plexus. Both Nav1.5 and Nav1.8 were expressed in ganglionated plexus with canonical neuronal markers. Sixteen canines were randomly administered either saline or the Nav1.8 blocker A‐803467. Electrophysiological study was compared between the 2 groups before and after 6‐hour rapid atrial pacing. Compared with the control group, administration of A‐803467 decreased the incidence of AF (87.5% versus 25.0%, P

Aims: The expression of sodium channel Nav1.8 in cardiac nervous systems has been identified, and variants of SCN10A that encodes Nav1.8 contribute to the development of Brugada syndrome (BrS) by modifying the function of Nav1.5 or directly reducing the sodium current. The aim of this study was to identify the frequency of SCN10A mutations in Japanese patients with BrS and to compare the phenotypical differences between patients with BrS and those who have other BrS-causative genes.Methods and Results: This study involved 240 Japanese probands who were clinically suspected with BrS and were negative for mutations in major BrS-related genes. We screened for the SCN10A gene using a high-resolution melting method and direct sequencing. In addition, we compared the clinical characteristics among the probands with gene mutations in SCN10A, 6 probands with CACNA1C and 17 probands with SCN5A. We identified six SCN10A variant carriers (2.5%): W189R, R844H (in two unrelated probands), N1328K, R1380Q, and R1863Q. Five were male. Four were symptomatic: one died following sudden cardiopulmonary arrest at age 35, one suffered ventricular fibrillation, and two had recurrent syncope. Compared with BrS patients carrying SCN5A or CACNA1C mutations, although there were no significant differences among them, symptomatic patients in the SCN10A group tended to be older than those in the other gene groups.Conclusion: In six BrS probands who carried SCN10A variants, most experienced severe arrhythmic attacks. It is of clinical importance to screen SCN10A mutations in BrS, although the functional significance of these variants remains unclear. [ABSTRACT FROM AUTHOR]

High-frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all isoforms in adult DRG, NaV1.6 is the main carrier of tetrodotoxin-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons, the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA-mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRG showed that NaVβ4 siRNA blocked the inflammation-induced increase in spontaneous activity of Aβ neurons and reduced repetitive firing and other measures of excitability. NaVβ4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression, and this was reversed by NaVβ4 siRNA, based on immunohistochemistry and Western blotting. NaVβ4 siRNA also reduced immunohistochemical NaV1.6 expression. Patch-clamp recordings of tetrodotoxin-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current, effects blocked by NaVβ4 siRNA. NaVβ4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing NaV1.6. [ABSTRACT FROM AUTHOR]

Gain-of-function mutations in the SCN10A gene (encoding the Na v 1.8 voltage gated sodium channel) have been reported in a small number of patients. All presented with predominantly painful sensory neuropathy, congruent with the expression of Na v 1.8 in nociceptive sensory neurons of the dorsal root ganglion. Only a few had mild autonomic symptoms, including dry eyes and mouth, orthostatic dizziness, palpitations, diarrhea and constipation. The underlying mechanism of the autonomic symptoms in these patients is unclear. We describe a 37-year-old woman with severe progressive gastroparesis and diffuse painful small fiber sensory neuropathy that started at age 32. Due to the severe dysphagia she could not ingest solid food, and lost eight kilograms. The gastroparesis was documented by esophageal manometry and gastric scintigraphy. The neuropathic pain started distally and then intensified and spread to most body areas. The patient harbored a novel heterozygous mutation: c.G4915A:p.D1639N in the SCN10A gene. To the best of our knowledge, this is the first description of such a phenotype due to a Na v 1.8 mutation. Thus, our study expands the clinical spectrum of Na v 1.8 associated disorders, and suggests that mutations in this sodium channel should be considered in patients with gastrointestinal motility dysfunction and painful neuropathy. [ABSTRACT FROM AUTHOR]

Dorsal root ganglion (DRG) neurons are important relay stations between the periphery and the central nervous system and are essential for somatosensory signaling. Reactive species are produced in a variety of physiological and pathophysiological conditions and are known to alter electric signaling. Here we studied the influence of reactive species on the electrical properties of DRG neurons from mice with the whole-cell patch-clamp method. Even mild stress induced by either low concentrations of chloramine-T (10 μM) or low-intensity blue light irradiation profoundly diminished action potential frequency but prolonged single action potentials in wild-type neurons. The impact on evoked action potentials was much smaller in neurons deficient of the tetrodotoxin (TTX)-resistant voltage-gated sodium channel Na1.8 (Na1.8), the channel most important for the action potential upstroke in DRG neurons. Low concentrations of chloramine-T caused a significant reduction of Na1.8 peak current and, at higher concentrations, progressively slowed down inactivation. Blue light had a smaller effect on amplitude but slowed down Na1.8 channel inactivation. The observed effects were less apparent for TTX-sensitive Na channels. Na1.8 is an important reactive-species-sensitive component in the electrical signaling of DRG neurons, potentially giving rise to loss-of-function and gain-of-function phenomena depending on the type of reactive species and their effective concentration and time of exposure. [ABSTRACT FROM AUTHOR]

Aims Brugada syndrome(BrS) remains genetically heterogeneous and is associated with slowed cardiac conduction.We aimed to identify genetic variation in BrS cases at loci associated with QRS duration. Methods and results Amulti-centre study sequenced seven candidate genes (SCN10A, HAND1, PLN, CASQ2, TKT, TBX3, and TBX5) in 156 Caucasian SCN5A mutation-negative BrS patients (80% male; mean age 48) with symptoms (64%) and/or a family history of sudden death (47%) or BrS (18%). Forty-nine variants were identified: 18 were rare (MAF ,1%) and non-synonymous; and 11/18 (61.1%), mostly in SCN10A, were predicted as pathogenic using multiple bioinformatics tools. Allele frequencies were compared with the Exome Sequencing and UK10K Projects. SKAT methods tested rare variation in SCN10A finding no statistically significant difference between cases and controls. Co-segregation analysis was possible for four of seven probands carrying a novel pathogenic variant. Only one pedigree (I671V/G1299A in SCN10A) showed co-segregation. The SCN10ASNPV1073 was, however, associated strongly with BrS [66.9 vs. 40.1% (UK10K)OR(95% CI) = 3.02 (2.35-3.87), P = 8.07 × 10-19]. Voltage-clamp experiments forNaV1.8 were performed for SCN10A common variants V1073, A1073, and rare variants of interest: A200V and I671V. V1073, A200V and I671V, demonstrated significant reductions in peak INa compared with ancestral allele A1073 (rs6795970). Conclusion Rare variants in the screened QRS-associated genes (including SCN10A) are not responsible for a significant proportion of SCN5A mutation negative BrS. The common SNP SCN10AV1073 was strongly associated with BrS and demonstrated loss of NaV1.8 function, as did rare variants in isolated patients. [ABSTRACT FROM AUTHOR]

The article presents a study that examined the association between early onset atrial fibrillation (AF) and common and rare SCN10A genetic variants. The study found that these variants can affect the function of the voltage-gated Nav1.8 sodium channel and influence susceptibility to AF. The methods of the study are discussed.

Aims To test the hypothesis that vulnerability to atrial fibrillation (AF) is associated with rare coding sequence variation in the SCN10A gene, which encodes the voltage-gated sodium channel isoform NaV1.8 found primarily in peripheral nerves and to identify potentially disease-related mechanisms in high-priority rare variants using in-vitro electrophysiology. Methods and results We re-sequenced SCN10A in 274 patients with early onset AF from the Vanderbilt AF Registry to identify rare coding variants. Engineered variants were transiently expressed in ND7/23 cells and whole-cell voltage clamp experiments were conducted to elucidate their functional properties. Resequencing SCN10A identified 18 heterozygous rare coding variants (minor allele frequency ≤1%) in 18 (6.6%) AF probands. Four probands were carriers of two rare variants each and 14 were carriers of one coding variant. Based on evidence of co-segregation, initial assessment of functional importance, and presence in ≥1 AF proband, three variants (417delK, A1886V, and the compound variant Y158D-R814H) were selected for functional studies. The 417delK variant displayed near absent current while A1886V and Y158D-R814H exhibited enhanced peak and late (INa-L) sodium currents; both Y158D and R818H individually contributed to this phenotype. Conclusion Rare SCN10A variants encoding Nav1.8 were identified in 6.6% of patients with early onset AF. In-vitro electrophysiological studies demonstrated profoundly altered function in 3/3 high-priority variants. Collectively, these data strongly support the hypothesis that rare SCN10A variants may contribute to AF susceptibility. [ABSTRACT FROM AUTHOR]

Aims Emerging evidences indicate that SCN10A/NaV1.8 is associated with cardiac conduction and atrial fibrillation, but the exact role of NaV1.8 in cardiac electrophysiology remains poorly understood. The present study was designed to investigate the effects of blocking NaV1.8 channels in cardiac ganglionated plexi (GP) on modulating cardiac conduction and atrial fibrillation inducibility in the canine model. Methods and results Thirteen mongrel dogs were randomly enrolled. Right cervical vagus nerve stimulation (VNS) was applied to determine its effects on the sinus rate, ventricular rate during atrial fibrillation, PR interval, atrial effective refractory period, and the cumulative window of vulnerability. The NaV1.8 blocker A-803467 (1 μmol/0.5 mL per GP, n = 7) or 5% DMSO/95% polyethylene glycol (0.5 mL per GP, n = 6, control) was injected into the anterior right GP and the inferior right GP. The effects of VNS on the sinus rate, ventricular rate, PR interval, atrial effective refractory period, and the cumulative window of vulnerability were significantly eliminated at 10, 35, and 90 min after A-803467 injection. In separate experiments (n = 8), A-803467 blunted the slowing of sinus rate with increasing stimulation voltage of the anterior right GP at 10 min after local injection. Conclusions Blockade of NaV1.8 channels suppresses the effects of VNS on cardiac conduction and atrial fibrillation inducibility, most likely by inhibiting the neural activity of the cardiac GP. [ABSTRACT FROM PUBLISHER]

Abstract: Therapeutic use of general sodium channel blockers, such as lidocaine, can substantially reduce the enhanced activity in sensory neurons that accompanies chronic pain after nerve or tissue injury. However, because these general blockers have significant side effects, there is great interest in developing inhibitors that specifically target subtypes of sodium channels. Moreover, some idiopathic small-fiber neuropathies are driven by gain-of-function mutations in specific sodium channel subtypes. In the current study, we focus on one subtype, the voltage-gated sodium channel 1.8 (Nav1.8). Nav1.8 is preferentially expressed in nociceptors, and gain-of-function mutations in Nav1.8 result in painful mechanical hypersensitivity in humans. Here, we used the recently developed gain-of-function Nav1.8 transgenic mouse strain, Possum, to investigate Nav1.8-mediated peripheral afferent hyperexcitability. This gain-of-function mutation resulted in markedly increased mechanically evoked action potential firing in subclasses of Aβ, Aδ, and C fibers. Moreover, mechanical stimuli initiated bursts of action potential firing in specific subpopulations that continued for minutes after removal of the force and were not susceptible to conduction failure. Surprisingly, despite the intense afferent firing, the behavioral effects of the Nav1.8 mutation were quite modest, as only frankly noxious stimuli elicited enhanced pain behavior. These data demonstrate that a Nav1.8 gain-of-function point mutation contributes to intense hyperexcitability along the afferent axon within distinct sensory neuron subtypes. [Copyright &y& Elsevier]

Aims SCN10A encodes the sodium channel Nav1.8 implicated by genome-wide association studies as a modulator of atrioventricular conduction (PR interval). In a cohort of patients with atrial fibrillation (AF), we examined whether there was an association between common variants in SCN10A and both the PR interval during normal sinus rhythm and the heart rate response during AF. Methods and results Patients prospectively enrolled in the Vanderbilt AF registry with electrocardiograms in normal sinus rhythm and/or AF within 1 year of enrollment were genotyped for two common SCN10A variants rs6795970 and rs12632942. Both variants were associated with the PR interval duration in a gene-dose effect on unadjusted analysis; after adjustment for the covariates age, gender, body mass index, hypertension, congestive heart failure, and medication usage, the association remained for rs6795970 only (P = 0.012, partial R2 = 0.0139). On unadjusted analysis, heart rate response during AF was associated with rs6795970 (P = 0.035, partial R2 = 0.015), but not with rs12632942 (P = 0.89), and neither association was significant after adjustment for covariates. Conclusion The common variant rs6795970 in SCN10A is associated with the PR interval duration among healthy patients and those with AF. In addition, this single nucleotide polymorphism trended towards an association with heart rate response during AF indicating the importance of this common SCN10A polymorphism as a marker of atrioventricular conduction. [ABSTRACT FROM PUBLISHER]

Background: Visceral sensory impulses are transmitted via C-fibers from the gastrointestinal tract to the central nervous system. The tetrodotoxinresistant (TTX-r) sodium channel, Na(V) 1.8/SNS (sensory-neuron specific), encoded by SCN10A, has been identified on C-fibers. We attempted to clarify the association between functional dyspepsia (FD) and SCN10A non-synonymous polymorphisms (2884 A>G, 3218 C>T and 3275 T>C). Methods: The study was performed in 642 subjects (345 with no symptoms and 297 with FD). We employed a multiplex polymerase chain reaction single-strand confirmation polymorphism (PCR-SSCP) method to detect the gene polymorphisms. Results: The 3218 CC homozygotes had a reduced risk for the development of FD [odds ratio (OR) 0.589; 95 % confidence interval (CI) 0.402-0.864; p = 0.0067]. In addition, both 2884 A>G and 3275 T>C, which were in linkage disequilibrium, were also associated with the development of FD ( p = 0.039 and 0.028, respectively). Each 2884 G carrier, 3218 CC homozygote, and 3275 C carrier had a reduced risk for the development of both epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). The subjects with the 2884 G allele, 3275 C allele, and no 3218 T allele had a reduced risk for FD (OR 0.618; 95 % CI 0.448-0.853; p = 0.0034). This haplotype was associated with a reduced risk for both EPS and PDS ( p = 0.0011 and 0.0056, respectively). In addition, there was a significant association between FD and this haplotype in Helicobacter pylori-negative subjects (OR 0.463; 95 % CI 0279-0.9768; p = 0.0029). Conclusion: We conclude that genetic polymorphisms of SCN10A are closely associated with FD (both EPS and PDS), especially in H. pylori-negative subjects, in Japanese. [ABSTRACT FROM AUTHOR]

Abstract: A vast diversity of salient cues is sensed by numerous classes of primary sensory neurons, defined by specific neuropeptides, ion channels, or cytoskeletal proteins. Recent evidence has demonstrated a correlation between the expression of some of these molecular markers and transmission of signals related to distinct sensory modalities (eg, heat, cold, pressure). Voltage-gated sodium channel Nav1.8 has been reported to be preferentially expressed in small-diameter unmyelinated sensory afferents specialized for the detection of noxious stimuli (nociceptors), and Nav1.8-Cre mice have been widely used to investigate gene function in nociceptors. However, the identity of neurons in which Cre-mediated recombination occurs in these animals has not been resolved, and whether expression of Nav1.8 in these neurons is dynamic during development is not known, rendering interpretation of conditional knockout mouse phenotypes problematic. Here, we used genetics, immunohistochemistry, electrophysiology, and calcium imaging to precisely characterize the expression of Nav1.8 in the peripheral nervous system. We demonstrate that 75% of dorsal root ganglion (DRG) neurons express Nav1.8-Cre, including >90% of neurons expressing markers of nociceptors and, unexpectedly, a large population (∼40%) of neurons with myelinated A fibers. Furthermore, analysis of DRG neurons’ central and peripheral projections revealed that Nav1.8-Cre is not restricted to nociceptors but is also expressed by at least 2 types of low-threshold mechanoreceptors essential for touch sensation, including those with C and Aβ fibers. Our results indicate that Nav1.8 underlies electrical activity of sensory neurons subserving multiple functional modalities, and call for cautious interpretation of the phenotypes of Nav1.8-Cre-driven conditional knockout mice. [Copyright &y& Elsevier]

Prior reports have identified associations between SCN10A and cardiac disorders, such as atrial fibrillation and Brugada syndrome. We evaluated SCN10A in 151 probands with ARVD/C. In this cohort, 10 putatively pathogenic SCN10A variants were identified, including a novel frameshift insertion. Despite a known role for the encoded protein in peripheral nerve function, the proband with the frameshift variant had no discernible neurological abnormalities. Arrhythmic phenotypes were not different between those with a rare variant in SCN10A and those without. The prevalence of rare variants in SCN10A was similar among ARVD/C probands with and without a desmosome mutation and similar among healthy Caucasian controls. These results indicate the absence of a primary role for SCN10A mutations in ARVD/C. [ABSTRACT FROM AUTHOR]