Mutations In Ion Channel Genes Research Articles

Perspective of Ion Channels in Prostate Cancer

Ion channels are membrane proteins, which play a great role in regulating cellular excitability. Alteration of ion channel may contribute to prostate cancer. This could be linked to inherited mutations of ion channel genes which alter channel’s biophysical properties, in a prostate cancer. It is an observed fact that genomic instability is the main cause as well as the major characteristics of prostate cancer. Prostate cancer cell genotypes are mainly characterized by uncontrolled metastasis, resistance to programmed cell death, sustained angiogenesis as well as tissue invasion and metastasis. It is known that genes encoding ion channels are affected in prostate cancer. The Membrane proteins which is involved in signaling in cell and among cells, for coupling of extracellular events with intracellular responses, and for maintaining intracellular ionic homeostasis ion channels which contribute to some extents to pathophysiological features of each prostate cancer.

Unravelling the Genetic Basis of Primary Aldosteronism.

Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms.

Functional evaluation of human ion channel variants using automated electrophysiology.

Patch clamp recording enabled a revolution in cellular electrophysiology, and is useful for evaluating the functional consequences of ion channel gene mutations or variants associated with human disorders called channelopathies. However, due to massive growth of genetic testing in medical practice and research, the number of known ion channel variants has exploded into the thousands. Fortunately, automated methods for performing patch clamp recording have emerged as important tools to address the explosion in ion channel variants. In this chapter, we present our approach to harnessing automated electrophysiology to study a human voltage-gated potassium channel gene (KCNQ1), which harbors hundreds of mutations associated with genetic disorders of heart rhythm including the congenital long-QT syndrome. We include protocols for performing high efficiency electroporation of heterologous cells with recombinant KCNQ1 plasmid DNA and for automated planar patch recording including data analysis. These methods can be adapted for studying other voltage-gated ion channels.

Engineered models of the human heart: Directions and challenges.

Human heart (patho)physiology is now widely studied using human pluripotent stem cells, but the immaturity of derivative cardiomyocytes has largely limited disease modeling to conditions associated with mutations in cardiac ion channel genes. Recent advances in tissue engineering and organoids have, however, created new opportunities to study diseases beyond “channelopathies.” These synthetic cardiac structures allow quantitative measurement of contraction, force, and other biophysical parameters in three-dimensional configurations, in which the cardiomyocytes in addition become more mature. Multiple cardiac-relevant cell types are also often combined to form organized cardiac tissue mimetic constructs, where cell-cell, cell-extracellular matrix, and paracrine interactions can be mimicked. In this review, we provide an overview of some of the most promising technologies being implemented specifically in personalized heart-on-a-chip models and explore their applications, drawbacks, and potential for future development.

Arrhythmic phenotypes in patients with left ventricular non-compaction cardiomyopathy

Abstract Background Identification of pts with left ventricular non-compaction cardiomyopathy (NCCM) at high risk of life-threatening arrhythmic events is focused on clinical and instrumental criteria. The genetic component is not taken into account when deciding on a strategy for preventive measures. Purpose To analyze life-threatening arrhythmic events in pts with the arrhythmic variant of NCCM and to identify genetic factors that may increase the risk of life-threatening arrhythmic events. Methods The study included 159 pts, among whom 58 had malignant ventricular arrhythmias (mean age 43.54±11.95 years, 34/24/58.6% male). The NCCM criteria were confirmed using Echocardiography and CMR. Mutation search was carried out by the next generation sequencing (NGS) in 21 pts with nonsustained ventricular tachycardia (NVT). Results During the follow-up period (median follow-up of 36 months), life-threatening arrhythmic events (documented sustained VT, SCD with successful resuscitation and CD implantation, SCD) were registered in 29 pts (50%), and 10 pts had CD implanted. As a result of sequencing, 23.8% (5 out of 21) of pts with NVT revealed rare genetic variants with uncertain clinical significance (VUS) in 3 genes encoding ion channel proteins: KCNQ1, KCNH2 (9.5%), RYR2 (9.5%). In 9 (42.9%) pts, 10 identified mutations were localized in the genes responsible for the synthesis of sarcomeric proteins: MYBPC3 (23.8%), MYH7 (23.8%). 12 genetic variants were found in overlapping phenotypes between NCCM, ARVC and DCM: PKP2, DSP, PLN, TRPM4 (14.3%), RBM20, LDB3 (9.5%), DPP6, DTNA, NEXN in 11 (52.4%) pts. In this group of pts, the most common (81.8% of cases) were life-threatening arrhythmic events that required surgical intervention: 6 pts were implanted with CD for primary prevention of SCD, two pts - CRT-D, two pts with systolic dysfunction were performed with OHT and one patient was implanted with the Accucinch transcatheter direct mitral valve annuloplasty system. In pts with mutations in sarcomeric protein genes, CD was implanted in 4.7% of cases, and in 14.3% of pts with mutations in ion channel genes (p<0.01). Conclusion The presence of mutations in genes that control the functioning of ion channels in complex overlapping genotypes is an additional risk factor for ventricular arrhythmias in patients with NCCM. Determining the genetic component opens up new opportunities for personalizing the risk stratification of pts with NCCM. Funding Acknowledgement Type of funding source: None

Transcriptome-wide single nucleotide polymorphisms related to electric organ discharge differentiation among African weakly electric fish species.

African weakly electric fish of the mormyrid genus Campylomormyrus generate pulse-type electric organ discharges (EODs) for orientation and communication. Their pulse durations are species-specific and elongated EODs are a derived trait. So far, differential gene expression among tissue-specific transcriptomes across species with different pulses and point mutations in single ion channel genes indicate a relation of pulse duration and electrocyte geometry/excitability. However, a comprehensive assessment of expressed Single Nucleotide Polymorphisms (SNPs) throughout the entire transcriptome of African weakly electric fish, with the potential to identify further genes influencing EOD duration, is still lacking. This is of particular value, as discharge duration is likely based on multiple cellular mechanisms and various genes. Here we provide the first transcriptome-wide SNP analysis of African weakly electric fish species (genus Campylomormyrus) differing by EOD duration to identify candidate genes and cellular mechanisms potentially involved in the determination of an elongated discharge of C. tshokwe. Non-synonymous substitutions specific to C. tshokwe were found in 27 candidate genes with inferred positive selection among Campylomormyrus species. These candidate genes had mainly functions linked to transcriptional regulation, cell proliferation and cell differentiation. Further, by comparing gene annotations between C. compressirostris (ancestral short EOD) and C. tshokwe (derived elongated EOD), we identified 27 GO terms and 2 KEGG pathway categories for which C. tshokwe significantly more frequently exhibited a species-specific expressed substitution than C. compressirostris. The results indicate that transcriptional regulation as well cell proliferation and differentiation take part in the determination of elongated pulse durations in C. tshokwe. Those cellular processes are pivotal for tissue morphogenesis and might determine the shape of electric organs supporting the observed correlation between electrocyte geometry/tissue structure and discharge duration. The inferred expressed SNPs and their functional implications are a valuable resource for future investigations on EOD durations.

Endoplasmic reticulum stress increases inflammatory cytokines in an epilepsy mouse model Gabrg2+/Q390X knockin: A link between genetic and acquired epilepsy?

Neuroinflammation is a major theme in epilepsy, which has been characterized in acquired epilepsy but is poorly understood in genetic epilepsy. γ-Aminobutyric acid type A receptor subunit gene mutations are significant causes of epilepsy, and we have studied the pathophysiology directly resulting from defective receptor channels. Here, we determined the proinflammatory factors in a genetic mouse model, the Gabrg2+/Q390X knockin (KI). We have identified increased cytokines in multiple brain regions of the KI mouse throughout different developmental stages and propose that accumulation of the trafficking-deficient mutant protein may increase neuroinflammation, which would be a novel mechanism for genetic epilepsy. We used enzyme-linked immunosorbent assay, immunoprecipitation, nuclei purification, immunoblot, immunohistochemistry, and confocal microscopy to characterize increased neuroinflammation and its potential causes in a Gabrg2+/Q390X KI mouse and a Gabrg2+/- knockout (KO) mouse, each associated with a different epilepsy syndrome with different severities. We found that proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 1-beta (IL-1β), and IL-6 were increased in the KI mice but not in the KO mice. A major underlying basis for the discrepancy in cytokine expression between the two mouse models is likely chronic mutant protein accumulation and endoplasmic reticulum (ER) stress. The presence of mutant protein dampened cytokine induction upon further cellular stimulation or external stress such as elevated temperature. Pharmacological induction of ER stress upregulated cytokine expression in the wild-type and KO but not in the KI mice. The increased cytokine expression was independent of seizure occurrence, because it was upregulated in both mice and cultured neurons. Together, these data demonstrate a novel pathophysiology for genetic epilepsy, increased neuroinflammation, which is a common mechanism for acquired epilepsy. The findings thus provide the first link of neuroinflammation between genetic epilepsy associated with an ion channel gene mutation and acquired epilepsy.

Exploring Neuronal Vulnerability to Head Trauma Using a Whole Exome Approach.

Brain injuries are associated with oxidative stress and a need to restore neuronal homeostasis. Mutations in ion channel genes, in particular CACNA1A, have been implicated in familial hemiplegic migraine (FHM) and in the development of concussion-related symptoms in response to trivial head trauma. The aim of this study was to explore the potential role of variants in other ion channel genes in the development of such responses. We conducted whole exome sequencing (WES) on16 individuals who developed a range of neurological and concussion-related symptoms following minor or trivial head injuries. All individuals were initially tested and shown to be negative for mutations in known FHM genes.Variants identified from the WES results were filtered to identify rare variants (minor allele frequency [MAF] <0.01) in genes related to neural processes as well as genes highly expressed in the brain using a combination of in silico prediction tools (SIFT, PolyPhen, PredictSNP, Mutation Taster, and Mutation Assessor). Rare (MAF <0.001) or novel heterozygous variants in 7 ion channel genes were identified in 37.5% (6/16) of the cases (CACNA1I, CACNA1C, ATP10A, ATP7B, KCNAB1, KCNJ10, and SLC26A4), rare variants in neurotransmitter genes were found in 2 cases (GABRG1 and GRIK1), and rare variants in 3 ubiquitin-related genes identified in 4 cases (SQSTM1, TRIM2, and HECTD1).In this study, the largest proportion of potentially pathogenic variants in individuals with severe responses to minor head trauma were identified in genes previously implicated in migraine and seizure-related autosomal recessive neurological disorders. Together with results implicating variants in the hemiplegic migraine genes, CACNA1A and ATP1A2, in severe head trauma response, our results support a role for heterozygous deleterious mutations in genes implicated in neurological dysfunction and potentially increasing the risk of poor response to trivial head trauma.

Mutation spectrum and health status in skeletal muscle channelopathies in Japan

Skeletal muscle channelopathies, including non-dystrophic myotonia and periodic paralysis, are rare hereditary disorders caused by mutations of various ion channel genes. To define the frequency of associated mutations of skeletal muscle channelopathies in Japan, clinical and genetic data of two academic institutions, which provides genetic analysis service, were reviewed. Of 105 unrelated pedigrees genetically confirmed, 66 pedigrees were non-dystrophic myotonias [CLCN1 (n = 30) and SCN4A (n = 36)], 11 were hyperkalemic periodic paralysis (SCN4A), and 28 were hypokalemic periodic paralysis [CACNA1S (n = 16) and SCN4A (n = 12)]. Of the 30 families with myotonia congenita, dominant form (Thomsen type) consisted 67%, and unique mutations, A298T, P480T, T539A, and M560T, not found in Western countries, were commonly identified in CLCN1. Hypokalemic periodic paralysis caused by SCN4A mutations consisted 43% in Japan, which was much higher than previous reports. Furthermore, the quality of life of the patients was assessed using the patient-reported outcome measures, SF-36 and INQoL, for 41 patients. This study indicated that the etiology of skeletal muscle channelopathies in Japan was not identical to previous reports from Western countries, and provided crucial information for genetics as well as future therapeutic interventions.

P341Life-threatening events in patients with non-compaction cardiomyopathy and mutations in ion channel genes

Abstract Purpose to analyze life-threatening events during follow-up in patients with non-compaction cardiomyopathy (NCCM) who have mutations in the genes responsible for the functioning of ion channels. Methods the study included 64 unrelated pts (aged 38.63 ± 14.72 years, 34/53.12% male, LVEF 43.02 ± 8.65%) with criteria of NCCM confirmed by imaging techniques (echocardiography (Jenni) and cardiovascular magnetic resonance (Petersen). Mutation search was carried out by the next generation sequencing (NGS). Pathogenic mutations or rare substitutions with possible clinical significance were found in 12 unrelated pts in the ion channel genes: KCNH2, KCNJ2, CACNA1C, RYR2, HCN4, TRPM4, PKP2, TRPM4. Mutations in other genes (PLN, DSP, NOTCH1, RBM20) were detected in 4 pts (1 pathogenic and 3 VUS). Results mutations in genes associated with long QT syndrome (LQTS) were found in 5 pts with NCCM: c.3107G &amp;gt; A (p.Gly1036Asp), с.2653С&amp;gt;T (p.Arg885Cys) in KCNH2 gene (16.7%); c.T28076 (p.F936C) in CaCNA1C gene (8.3%); c.1165G &amp;gt; C (p.Asp389Asn) in KCNJ2 gene (8.3%). There was no prolongation of the QTc interval &amp;gt; 480 msec on ECG; frequent episodes of nonsustained ventricular tachycardia (VT) were recorded on 24-hour ECG-monitoring. During the follow-up period (median follow-up of 2.4 years), two pts with mutations in KCNH2 genes with suddenly developed sustained VT were implanted with ICD. A 32-year-old patient with a mutation in CACNA1C gene and ST-elevation myocardial infarction of thromboembolic genesis underwent PCI. 58-year-old patient with widening of QRS &amp;gt; 130 msec and frequent paroxysms of nonsustained VT was implanted with CRT-D. An ICD was implanted in a 60-year-old patient with a mutation c.12665_12667del(p.4223del) in the RYR2 gene and suddenly developed a sustained VT. In the remaining two pts with RYR2 gene mutations c.12272C &amp;gt; T (p.Ala4091Val), c.12944G &amp;gt; A(p.Gly4315Glu), frequent episodes of nonsustained VT were recorded, which were corrected medically. Orthotopic heart transplantation and Accucinch transcatheter direct mitral valve annuloplasty system implantation were performed in two pts with ventricular tachyarrhythmias and severe systolic and diastolic dysfunction of the left ventricle with mutations c.3224T &amp;gt; C (p.Leu1075Pro), c.1459_1494del36 (p.Lys487_Leu498del) in the TRPM4 gene. In other pts with mutations in HCN4 (8.3%), DPP6 (8.3%), PKP2 (8.3%) genes ventricular tachyarrhythmias were treated with antiarrhythmic drugs. Conclusion the presence of mutations in the genes controlling the functioning of ion channels is an additional risk factor for adverse events in patients with NCCM.

Evidence of Progressive Brainstem Pathology after Repeated Seizure Exposure in a Novel Rat Model of SUDEP

Mutations in ion channel genes can alter neuronal excitability and have been linked to seizure disorders in humans. We previously established that a knockout rat model of Kcnj16, which encodes potassium channel subunit Kir5.1, on a Dahl SS background (SSKcnj16−/−) exhibits renal and respiratory impairments, in addition to audiogenic reflex epilepsy. While seizures can be considered benign acute events, patients with uncontrolled epilepsy are at high risk for Sudden Unexplained Death in Epilepsy (SUDEP), predicted to be due to cardiorespiratory failure following repeated seizures. The SSKcnj16−/− rat allows intractable epilepsy to be modeled with modifiable SUDEP risk by regulating seizure number and providing a controlled experimental environment with consistent occurrence of seizure‐induced death. During daily seizure exposure for up to 10 days, we observed progressive exacerbation of post‐ictal respiratory rate and heart rate suppression with spontaneous mortality in 33% of SSKcnj16−/− rats within hours of a seizure. We tested the hypothesis that repeated seizures induces neuroinflammation and dysregulation of adenosine (ADO) and serotonin (5HT) within brainstem cardiorespiratory nuclei, which may contribute to progressive cardiorespiratory suppression and subsequent mortalities in SSkcnj16−/− rats. Quantification of brainstem neurochemicals by HPLC revealed increased ADO and decreased 5HT in seizure‐exposed compared to naïve SSkcnj16−/− rats. These findings appeared to be brainstem‐specific as ADO levels in the cortex of seizure exposed rats were decreased. Western blot analyses of whole brainstem lysates showed trends toward decreased expression of ADO kinase (ADK) and A1 receptor (A1R) in seizure‐exposed rats. We used immunofluorescent staining and confocal imaging to label and quantify total 5HT, serotonergic neurons (tryptophan hydroxylase, TPH), microglia (Iba1), astrocytes (GFAP), total neurons (NeuN), and total nuclei (DAPI) in respiratory brainstem nuclei of SSkcnj16−/− rats exposed to 0, 3, or 10 seizures (n=2/group). Consistent with our HPLC data, 5HT staining was decreased in the pre‐Bötzinger Complex (preBötC), Nucleus Ambiguus (NA) and medullary Raphe (MR) of seizure‐exposed rats, which also showed fewer TPH‐positive neurons in MR. Staining also revealed that seizures may induce brainstem inflammation that resulted in transient increases reactive microglia and progressive astrogliosis in these rats. SSkcnj16−/− rats showed increased Iba1 after 3 seizures but no change after 10 seizures in the preBötC, NA, MR and nucleus of the solitary tract (NTS). GFAP progressively increased after 3 and 10 seizures in preBötC, NTS, and MR. Further studies will focus on validating these finding by increasing the number of animals in experimental groups and evaluating additional inflammatory markers. This preliminary data suggests that dysregulation of ADO and 5HT and/or inflammation in respiratory brainstem nuclei may mediate respiratory suppression and subsequent mortality associated with repeated seizure exposure in SSKcnj16−/− rats, which may have central relevance to the pathophysiology of SUDEP which remains poorly understood.Support or Funding InformationR01 HL122358

Pathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism

Human primary aldosteronism (PA) can be caused by mutations in several ion channel genes but mouse models replicating this condition are lacking. We now show that almost all known PA-associated CLCN2 mutations markedly increase ClC-2 chloride currents and generate knock-in mice expressing a constitutively open ClC-2 Cl− channel as mouse model for PA. The Clcn2op allele strongly increases the chloride conductance of zona glomerulosa cells, provoking a strong depolarization and increasing cytoplasmic Ca2+ concentration. Clcn2op mice display typical features of human PA, including high serum aldosterone in the presence of low renin activity, marked hypertension and hypokalemia. These symptoms are more pronounced in homozygous Clcn2op/op than in heterozygous Clcn2+/op mice. This difference is attributed to the unexpected finding that only ~50 % of Clcn2+/op zona glomerulosa cells are depolarized. By reproducing essential features of human PA, Clcn2op mice are a valuable model to study the pathological mechanisms underlying this disease.

Clinical features and ion channel gene mutations analysis in 17 cases of early-onset epileptic encephalopathy

Objective To analyze the clinical characteristics and gene mutations of early-onset epileptic encephalopathy(EOEE) caused by ion channel gene mutation, to identify the etiology, to guide the treatment and to provide the basis for genetic counseling. Methods The clinical data from 17 children with EOEE caused by ion channel gene mutation and the peripheral blood of the children and their parents were collected from June 2014 to May 2018 at the Department of Neurology, Tianjin Children′s Hospital.Epilepsy gene sequencing was performed by using disease gene targeting second generation sequencing technology.The mutation of pathogenic ion channel gene was found.The confirmed mutations were verified by Sanger sequencing and the source of the mutation was identified. Results Among 17 case with EOEE, 3 cases had genetic mutation, and 14 cases had denovo mutations.Dravet syndrome was found in 8 cases (47.1%), there were SCN1A gene missense mutation in 5 cases, SCN1A gene nonsense mutation in 3 cases, KCNQ2 gene missense mutation in 1 case (5.9%) and non-specific epileptic encephalopathy in 8 cases (47.1%). SCN2A gene missense mutation, SCN4A gene missense mutation, SCN8A gene missense mutation, KCNQ2 gene missense mutation and KCNH gene missense mutation were found in suspected pathogenic mutations.There were 1 missense mutation out of 5 genes, 1 missense mutation of CACNA1A gene, 1 missense mutation of GRIN2A gene and 1 missense mutation of GRIN3A gene.Seventeen patients were treated with 2 or more antiepileptic drugs, 4 with ketogenic diet and 1 with vitamin B6 supplementation.During 11 to 96 months of follow-up, seizures were completely controlled in 3 cases (17.6%), decreased in 7 cases (41.2%) by more than 50%, and decreased in 7 cases (41.2%) by less than 50%. Conclusions The clinical phenotypes for children with unexplained EOEE are varied, and gene mutations of ion cha-nnel are most common.Some gene sites are denovo mutations which have not been reported such as missense mutation for 3 case SCN1A gene, 1 case SCN2A gene, 1 case CACNA1A gene, 1 case KCNH5 gene, and nonsense mutation for 2 case SCN1A gene, which have enriched the mutation spectrum of EOEE. Key words: Early-onset epileptic encephalopathy; Ion channel; Etiology; Gene mutation

A rare form of ion channel gene mutation identified as underlying cause of generalized epilepsy

The advances in molecular genetic methods has lead to the discovery of the genetic alterations that underlie the etiology of most diseases previously held to be idiopathic. Targeted genetic examination of a pediatric male patient showing a normal intellect, an extended area of skin hypopigmentation, and suffering from generalized epilepsy displaying a switch in epilepsy syndrome during the course of the disease towards a neurocutaneous syndrome was unsuccessful. Whole-exome sequencing identified a heterozygous missense mutation in a potassium chloride cotransporter gene, which together with the phenotype underscores the diagnosis of an epilepsy syndrome known in the literature as idiopathic generalized epilepsy type 14. Orv Hetil. 2019; 160(21): 835-838.

Dual separable feedback systems govern firing rate homeostasis.

Firing rate homeostasis (FRH) stabilizes neural activity. A pervasive and intuitive theory argues that a single variable, calcium, is detected and stabilized through regulatory feedback. A prediction is that ion channel gene mutations with equivalent effects on neuronal excitability should invoke the same homeostatic response. In agreement, we demonstrate robust FRH following either elimination of Kv4/Shal protein or elimination of the Kv4/Shal conductance. However, the underlying homeostatic signaling mechanisms are distinct. Eliminating Shal protein invokes Krüppel-dependent rebalancing of ion channel gene expression including enhanced slo, Shab, and Shaker. By contrast, expression of these genes remains unchanged in animals harboring a CRISPR-engineered, Shal pore-blocking mutation where compensation is achieved by enhanced IKDR. These different homeostatic processes have distinct effects on homeostatic synaptic plasticity and animal behavior. We propose that FRH includes mechanisms of proteostatic feedback that act in parallel with activity-driven feedback, with implications for the pathophysiology of human channelopathies.

Cardiac conduction defects.

Defects in cardiac electric impulse formation or conduction can lead to an irregular beat (arrhythmia) that can cause sudden death without any apparent cause or after stress. In the following sections, we describe the genetic disorders associated with primary cardiac conduction defects, primarily caused by mutations in ion channel genes. Primary indicates that these disorders are not caused by drugs and are not secondary to other disorders like cardiomyopathies (described in the next section). (www.actabiomedica.it)

Turning a negative into a positive

In this volume of The Journal, Tester et al described the results of a large study employing whole exome sequencing for rare variants in sudden infant death syndrome (SIDS). These investigators carried out whole exome sequencing on 278 cases of SIDS and compared the results to 973 ethnic-matched controls. One Reviewer remarked, “Many of us have been waiting for this paper after its initial presentation in oral form. There was a sharp intake of breath around the room as an essentially negative report came out.” Indeed, while no exome-wide significant differences (P < 2.5 × 10−6) in burden of ultra-rare variants was detected for any genes this is still a notable effort. This was a substantial undertaking and represents important results for the research community, the clinical community, and the families of patients with sudden infant death syndrome. Although this negative result suggests that there is not a readily discernible monogenic cause of SIDS, it does not rule out genetics per se. Many complex disorders are due to alterations in multiple genes in networks and pathways. That remains to be explored in SIDS. The authors also note that there are some rare “monogenic causes of SIDS including mutations in ion-channel genes, SCN5A and SCN4A.” Thus ultra-rare genetic variations in the exome do not represent an abundant explanation underlying the etiology of SIDS. It is possible that additional studies may identify SIDS susceptibility genes with varying penetrance but it remains likely from these data that monogenic disorders stemming from cardiac channelopathies and other established sudden death pathways will comprise less than 10% of all SIDS. This very substantial effort, albeit negative, has contributed important work in this field. Negative findings have garnered great controversy and publicity in science. The longstanding bias against publication of negative findings is beginning to be reversed by recognition of the importance of such results. A recent Editorial describing negative studies in cancer research has pointed out the importance of recognition of negative trials (JAMA Oncol 2016;2:865-6). Obvious benefits include dissuading individuals from unnecessary duplication. Negative trials may identify treatments with less morbidity and less cost compared to newer, more intensive therapies that turn out to lack benefit. Negative trials in intensive therapy for breast cancer have led to improvements and recognition that, in some patients, more radical treatments are unnecessary. The authors of the Editorial recommend that, for negative trials, it is important to include their impact on patient care. In the case of this negative result for SIDS, family appreciation of, in this case lack of, genetic etiologies for the great majority of SIDS cases may provide some comfort or at least enhanced understanding. Article page 423 ▶ Exome-Wide Rare Variant Analyses in Sudden Infant Death SyndromeThe Journal of PediatricsVol. 203PreviewTo determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. Full-Text PDF

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Seizure disorders are very common and affect 3% of the general population. The recurrent unprovoked seizures that are also called epilepsies are highly diverse as to both underlying genetic basis and clinic presentations. Recent genetic advances and sequencing technologies indicate that many epilepsies previously thought to be without known causes, or idiopathic generalized epilepsies (IGEs), are virtually genetic epilepsy as they are caused by genetic variations. IGEs are estimated to account for ∼15-20% of all epilepsies. Initially IGEs were primarily considered channelopathies, because the first genetic defects identified in IGEs involved ion channel genes. However, new findings indicate that mutations in many non ion channel genes are also involved in addition to those in ion channel genes. Interestingly, mutations in many genes associated with epilepsy affect GABAergic signaling, a major biological pathway in epilepsy. Additionally, many antiepileptic drugs work via enhancing GABAergic signaling. Hence, the review will focus on the mutations that impair GABAergic signaling and selectively discuss the newly identified STXBP1, PRRT2, and DNM1 in addition to those long-established epilepsy ion channel genes that also impair GABAergic signaling like SCN1A and GABAA receptor subunit genes. GABAergic signaling includes the pre- and post- synaptic mechanisms. Some mutations, such as STXBP1, PRRT2, DNM1, and SCN1A, impair GABAergic signaling mainly via pre-synaptic mechanisms while those mutations in GABAA receptor subunit genes impair GABAergic signaling via post-synaptic mechanisms. Nevertheless, these findings suggest impaired GABAergic signaling is a converging pathway of defects for many ion channel or non ion channel mutations associated with genetic epilepsies.

Ion Channels in Cancer: Are Cancer Hallmarks Oncochannelopathies?

Genomic instability is a primary cause and fundamental feature of human cancer. However, all cancer cell genotypes generally translate into several common pathophysiological features, often referred to as cancer hallmarks. Although nowadays the catalog of cancer hallmarks is quite broad, the most common and obvious of them are 1) uncontrolled proliferation, 2) resistance to programmed cell death (apoptosis), 3) tissue invasion and metastasis, and 4) sustained angiogenesis. Among the genes affected by cancer, those encoding ion channels are present. Membrane proteins responsible for signaling within cell and among cells, for coupling of extracellular events with intracellular responses, and for maintaining intracellular ionic homeostasis ion channels contribute to various extents to pathophysiological features of each cancer hallmark. Moreover, tight association of these hallmarks with ion channel dysfunction gives a good reason to classify them as special type of channelopathies, namely oncochannelopathies. Although the relation of cancer hallmarks to ion channel dysfunction differs from classical definition of channelopathies, as disease states causally linked with inherited mutations of ion channel genes that alter channel's biophysical properties, in a broader context of the disease state, to which pathogenesis ion channels essentially contribute, such classification seems absolutely appropriate. In this review the authors provide arguments to substantiate such point of view.

Knockout of Kcnj16 (Kir5.1) in Dahl Salt‐Sensitive Rats Produces Seizure Phenotype

Kir5.1 is a member of an inwardly rectifying potassium (Kir) channel family notably present in the kidney and brain. We previously established that a knockout rat model of Kcnj16 (gene encoding Kir5.1) on a Dahl salt‐sensitive background (SSKcnj16−/−) exhibits a severe cardiovascular phenotype (Palygin et al., JCI Insight, 2017). Mutations in ion channel genes can alter neuronal excitability and mutations in Kir genes have been linked to seizure disorders in humans. Since Kir5.1 is known to be expressed in the brain and may contribute to neuronal membrane potential and spatial potassium buffering, we hypothesized that in addition to cardiovascular and renal dysfunction, neurological phenotypes, including seizures, would be prevalent in the SSKcnj16−/−rats. We found that SSKcnj16−/− rats (but not control SS rats) experience tonic‐clonic seizures when exposed to a 10 kHz tone (86 dB for 2 min), whereas other frequencies (0.1 or 1 kHz) did not elicit seizures. When exposed to the seizure‐inducing acoustic stimulus once/day for 10 days, we noted that SSKcnj16−/− rats experienced a seizure in response to 92% of stimuli. SSKcnj16−/− rats also showed spontaneous mortality within hours after a stimulus with a survival rate of 67% (N=21) for the duration of the 10 day protocol. Control rats (N=10) had no incidence of seizure or death during the 10 days of acoustic stimulation. We found no difference among male and female SSKcnj16−/− rats, where both sexes had a similar audiogenic seizure response and reduced survival. Behavioral tests including a modified Irwin screen and open field test revealed that before and after seizure stimulation SSKcnj16−/− rats tended to have altered activity levels, gait, piloerection, and respiration rates. Analysis of blood electrolytes revealed critically low serum potassium levels in SSKcnj16−/− compared to SS controls, a difference that appeared to be exacerbated by repeated seizures. We hypothesize that seizures may be intensifying potassium imbalance and disrupting the homeostasis that is particularly essential for excitable cells such as neurons. We conclude that knockout of Kir5.1 leads to distinct neurological phenotypes including a seizure disorder and subsequent spontaneous death, which may have relevance to channelopathies associated with seizure disorders in humans.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.