Mutations In Ion Channel Genes Research Articles

Genetic characterization of drug-induced long QT syndrome in a large prospective cohort

Abstract Introduction Drug-induced long QT syndrome (DI-LQTS) is a clinical entity with a poorly defined etiopathogenesis. Purpose The objective of the study was to determine the genetic basis of a prospective cohort of patients with DI-LQTS in the setting of a tertiary hospital center. Methods Prospective observational study with consecutive inclusion of patients with the diagnosis of DI-LQTS according to standard criteria, in a tertiary hospital, between 2018 and 2022. A genetic study was performed through massive DNA sequencing to identify variants in known genes associated with cardiopathy, arrhythmogenic and cardiomyopathy. Results 86 patients (age 65±15 years, 59% men) were included. The mean corrected QT interval (QTc) of the entire cohort was 543±56 ms. The drugs associated with QTc interval prolongation were: psychotropics 51%, antiarrhythmics 38%, anesthetics 30%, antibiotics 16%, antineoplastics 5%, others 4%. Twenty-one patients (24%) presented with ventricular arrhythmias at the time of drug-induced QTc prolongation: 10 (12%) ventricular fibrillation, 7 (8%) sustained ventricular tachycardia, 3 (3%) non-sustained ventricular tachycardia, 1 (1%) frequent ventricular premature beats. Genetic information was obtained in 83 (97%) patients. 17 pathogenic mutations associated with heart disease were identified in 15 (18%) patients: 4 (5%) patients with 5 mutations in ion channel genes (KCNE1, KCNE1B, KCNH2, RYR1, RYR2), and 12 (14%) patients with 12 mutations in genes associated with cardiomyopathy (NF1, PKD2, ABCC6, TTN, FHOD3, MYO6, COL11A1, CCDC40, CRELD1, COL4A1). Two patients had 2 pathogenic mutations each, one of them with both mutations associated with channelopathy, and another with a mutation associated with channelopathy and a second mutation related to cardiomyopathy. Only 1 patient carrying a pathogenic mutation related to cardiomyopathy had a clear phenotype, while in 3 carrier patients there was a history of transient systolic dysfunction, 2 due to tachycardiocardiopathy and 1 due to peripartum cardiomyopathy. The identification of a pathogenic mutation was not related to significant differences in QTc interval prolongation (544±63 vs 542±55 ms) or risk of ventricular arrhythmias (26% vs 24%). Conclusions The genetic basis of drug-induced long QT syndrome is essentially different from that of the congenital form of the disease. The identification of pathogenic mutations in genes associated with cardiomyopathy is relatively frequent, while those associated with ion channel genes are uncommon.

Reduction of Kcnt1 is therapeutic in mouse models of SCN1A and SCN8A epilepsy.

Developmental and epileptic encephalopathies (DEEs) are severe seizure disorders with inadequate treatment options. Gain- or loss-of-function mutations of neuronal ion channel genes, including potassium channels and voltage-gated sodium channels, are common causes of DEE. We previously demonstrated that reduced expression of the sodium channel gene Scn8a is therapeutic in mouse models of sodium and potassium channel mutations. In the current study, we tested whether reducing expression of the potassium channel gene Kcnt1 would be therapeutic in mice with mutation of the sodium channel genes Scn1a or Scn8a. A Kcnt1 antisense oligonucleotide (ASO) prolonged survival of both Scn1a and Scn8a mutant mice, suggesting a modulatory effect for KCNT1 on the balance between excitation and inhibition. The cation channel blocker quinidine was not effective in prolonging survival of the Scn8a mutant. Our results implicate KCNT1 as a therapeutic target for treatment of SCN1A and SCN8A epilepsy.

Novel combinations of variations in KCNQ1 were associated with patients with long QT syndrome or Jervell and Lange-Nielsen syndrome

ObjectivesLong QT syndrome (LQTS) is one of the primary causes of sudden cardiac death (SCD) in youth. Studies have identified mutations in ion channel genes as key players in the pathogenesis of LQTS. However, the specific etiology in individual families remains unknown.MethodsThree unrelated Chinese pedigrees diagnosed with LQTS or Jervell and Lange-Nielsen syndrome (JLNS) were recruited clinically. Whole exome sequencing (WES) was performed and further validated by multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing.ResultsAll of the probands in our study experienced syncope episodes and featured typically prolonged QTc-intervals. Two probands also presented with congenital hearing loss and iron-deficiency anemia and thus were diagnosed with JLNS. A total of five different variants in KCNQ1, encoding a subunit of the voltage-gated potassium channel, were identified in 3 probands. The heterozygous variants, KCNQ1 c.749T > C was responsible for LQTS in Case 1, transmitting in an autosomal dominant pattern. Two patterns of compound heterozygous variants were responsible for JLNS, including a large deletion causing loss of the exon 16 and missense variant c.1663 C > T in Case 2, and splicing variant c.605-2 A > G and frame-shift variant c.1265del in Case 3. To our knowledge, the compound heterozygous mutations containing a large deletion and missense variant were first reported in patients with JLNS.ConclusionOur study expanded the LQTS genetic spectrum, thus favoring disease screening and diagnosis, personalized treatment, and genetic consultation.

Ion channels in neurodevelopment: lessons from the Integrin-KCNB1 channel complex.

Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes. Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide. Epilepsies are triggered by an imbalance between excitatory and inhibitory conductances. However, pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function variants, all able to trigger epilepsy. Furthermore, certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype. This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought. Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox. The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes, including neuronal migration, neurite outgrowth, and synapse formation. Thus, pathogenic channel mutants can not only cause epileptic disorders by altering excitability, but further, by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.

1064 LONG QTC IN HCM: A CONSEQUENCE OF MYOCARDIAL HYPERTROPHY OR A DISTINCT GENETIC DISEASE?

Abstract Hypertrophic cardiomyopathy (HCM) is an autosomal dominant condition, characterized by the presence of unexplained left ventricular hypertrophy. This condition is usually associated with electrocardiographic abnormalities including QTc prolongation reported in the 13% of HCM patients. The main explanation for QTc prolongation in HCM is myocardial hypertrophy and the related structural damage. However, mechanisms other than myocardial hypertrophy, including long QT syndrome (LQTS) gene mutations, may also be involved. The addictive effect of 2 disease-causing mutations has been already reported in other pathological conditions. In the present study we investigated the possible co-inheritance of pathogenic variants associated with both LQTS and HCM, exploring the hypothesis of a distinct genetic basis underlying QTc prolongation in HCM. For this purpose, we considered a cohort of 150 HCM patients carrying pathogenic variants in sarcomeric genes. Out of them we selected 25 patients carrying a QTc prolongation not explained by any other cause (drugs, etc). The QTc was considered prolonged if greater than 450 ms in males and greater than 470 ms in females. NGS analysis was performed with Illumina TrueSight Cardio panel genes on Illumina MiniSeq platform to evaluate the presence of pathogenetic variants in LQTS related genes. We identified pathogenic/likely pathogenic variants in LQTS related gene KCNQ1 (c.1781G>A, p. Arg594Gln; c.532G>A, p. Ala178Thr) in two patients (8%) and uncertain significant variants in SCN5A, KCNJ5, AKAP9 and ANK2 in four patients (16%). Although the results of our study are limited by the small number of patients included in the analysis, they highlight a minor contribution of LQTS genes in HCM patients with a QTc prolongation. The screening for ion channel gene mutations should be considered in HCM patients with QTc prolongation, not explained by any other cause. This strategy may be important for risk stratification and treatment planning.

GABRG2 C588T Polymorphism Is Associated with Idiopathic Generalized Epilepsy but Not with Antiepileptic Drug Resistance in Pakistani Cohort.

Idiopathic generalized epilepsy (IGE) is the most prevalent type of epilepsy with genetic origin. Mutations in ion channel genes have been identified as a common cause of IGE. Several studies have reported various epilepsy risk variants of GABRG2 (gamma-aminobutyric acid type A receptor subunit gamma2 subunit) gene in different ethnic groups, but the results are inconsistent. The purpose of this case-control research is to determine if GABRG2 polymorphisms contribute to IGE susceptibility and antiepileptic drug resistance in Pakistani population. For this purpose, we genotyped exon2, exon5 (C540T and C588T), exon7 (T813C), exon8 (K289M), and exon9 of GABRG2 gene by restriction fragment length polymorphism and Sanger's sequencing in 87 drug-responsive idiopathic generalized epilepsy patients, 55 drug-resistant epilepsy patients, and 83 healthy controls. Restriction fragment length polymorphism (RFLP) and sequencing results indicated only C588T polymorphism in the studied subjects. The comparison of genotypic and allelic frequencies showed significant differences between IGE patients and control groups (P = 0.008 and odds ratio = 4.2) and nonsignificant association of C588T polymorphism in antiseizure medication-resistant patients (P = 0.9). Our findings showed that C588T polymorphism of GABRG2 is a risk variant for IGE in Pakistani population. Further studies are required to validate the results.

Periodic paralysis due to cumulative effects of rare variants in SCN4A with small functional alterations.

Mutations in the SCN4A gene encoding a voltage-gated sodium channel (Nav1.4) cause hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). Typically, both HyperPP and HypoPP are considered as monogenic disorders caused by a missense mutation with a large functional effect. However, a few cases with atypical periodic paralysis phenotype have been caused by multiple mutations in ion-channel genes expressed in skeletal muscles. In this study we investigated the underlying pathogenic mechanisms in such cases. We clinically assessed two families: proband 1 with HyperPP and proband 2 with atypical periodic paralysis with hypokalemia. Genetic analyses were performed by next-generation sequencing and conventional Sanger sequencing, followed by electrophysiological analyses of the mutant Nav1.4 channels expressed in human embryonic kidney 293T (HEK293T) cells using the whole-cell patch-clamp technique. In proband 1, K880del was identified in the SCN4A gene. In proband 2, K880del and a novel mutation, R1639H, were identified in the same allele of the SCN4A gene. Functional analyses revealed that the K880del in SCN4A has a weak functional effect on hNav1.4, increasing the excitability of the sarcolemma, which could represent a potential pathogenic factor. Although R1639H alone did not reveal functional changes strong enough to be pathogenic, Nav1.4 with both K880del and R1639H showed enhanced activation compared with K880del alone, indicating that R1639H may modify the hNav1.4 channel function. A cumulative effect of variants with small functional alterations may be considered as the underpinning oligogenic pathogenic mechanisms for the unusual phenotype of periodic paralysis.

Functional evaluation of the tachycardia patient-derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variant.

Tachycardia is characterized by high beating rates that can lead to life-threatening fibrillations. Mutations in several ion-channel genes were implicated with tachycardia; however, the complex genetic contributors and their modes of action are still unclear. Here, we investigated the influence of an SCN5A gene variant on tachycardia phenotype by deriving patient-specific iPSCs and cardiomyocytes (iPSC-CM). Two tachycardia patients were genetically analyzed and revealed to inherit a heterozygous p.F1465L variant in the SCN5A gene. Gene expression and immunocytochemical analysis in iPSC-CMs generated from patients did not show any significant changes in mRNA levels of SCN5A or gross NaV1.5 cellular mislocalization, compared to healthy-derived iPSC-CMs. Electrophysiological and contraction imaging analysis in patient iPSC-CMs revealed intermittent fibrillation-like states, occasional arrhythmic events, and sustained high-paced contractions that could be selectively reduced by flecainide treatment. The patch-clamp analysis demonstrated a negative shift in the voltage-dependent activation at the patient-derived iPSC-CMs compared to the healthy control line, suggestive of a gain-of-function activity associated with the SCN5A+/p.F1465L variant. Our patient-derived iPSC-CM model recapitulated the clinically relevant characteristics of tachycardia associated with a novel pathogenic SCN5A+/p.F1465L variant leading to altered Na+ channel kinetics as the likely mechanism underlying high excitability and tachycardia phenotype.

Vulnerability of Human Cerebellar Neurons to Degeneration in Ataxia-Causing Channelopathies.

Mutations in ion channel genes underlie a number of human neurological diseases. Historically, human mutations in ion channel genes, the so-called channelopathies, have been identified to cause episodic disorders. In the last decade, however, mutations in ion channel genes have been demonstrated to result in progressive neurodegenerative and neurodevelopmental disorders in humans, particularly with ion channels that are enriched in the cerebellum. This was unexpected given prior rodent ion channel knock-out models that almost never display neurodegeneration. Human ataxia-causing channelopathies that result in even haploinsufficiency can result in cerebellar atrophy and cerebellar Purkinje neuron loss. Rodent neurons with ion channel loss-of-function appear to, therefore, be significantly more resistant to neurodegeneration compared to human neurons. Fundamental differences in susceptibility of human and rodent cerebellar neurons in ataxia-causing channelopathies must therefore be present. In this review, we explore the properties of human neurons that may contribute to their vulnerability to cerebellar degeneration secondary to ion channel loss-of-function mutations. We present a model taking into account the known allometric scaling of neuronal ion channel density in humans and other mammals that may explain the preferential vulnerability of human cerebellar neurons to degeneration in ataxia-causing channelopathies. We also speculate on the vulnerability of cerebellar neurons to degeneration in mouse models of spinocerebellar ataxia (SCA) where ion channel transcript dysregulation has recently been implicated in disease pathogenesis.

Analysis of a Family with Brugada Syndrome and Sudden Cardiac Death Caused by a Novel Mutation of SCN5A.

Background Brugada syndrome is a hereditary cardiac disease associated with mutations in ion channel genes. The clinical features include ventricular fibrillation, syncope, and sudden cardiac death. A family with Brugada syndrome with sudden cardiac death was analyzed to locate the associated mutation in the SCN5A gene. Methods and Results Three generations of a Han Chinese family with Brugada syndrome were recruited in the study; their clinical phenotype data were collected and DNA samples extracted from the peripheral blood. Next-generation sequencing was carried out in the proband, and candidate genes and mutations were screened using the full exon capture technique. The family members who participated in the survey were tested for possible mutations using Sanger sequencing. Six family members were diagnosed with Brugada syndrome, including four asymptomatic patients. A newly discovered heterozygous mutation in the proband was located in exon 25 of SCN5A (NM_000335.5) at c.4313dup(p.Trp1439ValfsTer32). Among the surviving family members, only those with a Brugada wave on their electrocardiogram carried the c.4313dup(p.Trp1439ValfsTer32) variant. Bioinformatics prediction revealed that the frameshift of the c.4313dup (p.Trp1439ValfsTer32) mutant led to a coding change of 32 amino acids, followed by a stop codon, resulting in a truncated protein product. Conclusion The newly discovered mutation site c.4313dup(p.Trp1439ValfsTer32) in exon 25 of SCN5A may be the molecular genetic basis of the family with Brugada syndrome.

Successful medical treatment of west syndrome with a KCNA2 variant: a case report

BackgroundWest syndrome is a devastating disorder characterized by a triad of epileptic spasms, abnormal electroencephalography (EEG), and developmental arrest or psychomotor delay. In addition to early diagnosis, knowing the etiology of the condition is also important for its treatment. Among various etiologies, the genetic factors, especially mutations of ion channel genes, are very common and strongly linked to West syndrome.Case presentationA boy who had epileptic spasms from the age of 4 months was diagnosed with West syndrome based on the clinical manifestation and EEG results in Shenzhen Children’s Hospital in June 2019. Trios whole-exome sequencing (WES) test and protein structural model prediction were performed. We also reviewed the clinical and genetic features of this syndrome and the mechanisms of action of topiramate (TPM) by literature search in databases of Online Mendelian Inheritance in Man, Clinical Genome Resource, PubMed, Chinese National Knowledge Infrastructure and Wanfang database using keywords “KCNA2” “West syndrome” and “Topiramate” by December 2020. The relationship between the effect of TPM and the pathogenesis of the KCNA2 variant was also assessed. The WES test revealed c.244C > T/p. Arg82Cys varaint of KCNA2 (NM_004974.3) in this patient, and Sanger sequencing identified this was a de novo mutation. As far as we know, this is the first report of the c.244C > T/p. Arg82Cys variant in KCNA2, which was likely a pathogenic mutation. The seizures were successfully controlled for 10 months by TPM after failure of sodium valproate, large doses of vitamin B6, and adrenocorticotropic hormone. We speculate that the therapeutic effect of TPM in this patient is partially due to the inhibition of carbonic anhydrase.ConclusionsMutations in the KCNA2 gene should be considered for patients with West syndrome. The TPM treatment is probably effective for KCNA2-associated disorders.

A246 GASTROINTESTINAL ADVERSE EVENTS OF CANNABINOIDS IN PEDIATRIC POPULATIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS

BackgroundUse of therapeutic cannabinoids in the pediatric population has increased in recent years within areas of epilepsy, palliative care, and cancer. Given the endocannabinoid system plays a crucial role in gastrointestinal (GI) homeostasis, exogenous cannabinoids have the potential to develop GI related side effects. While some GI adverse events have been reported with the use of therapeutic cannabinoids, the full profile of GI adverse events in the pediatric population is still unknown.AimsTo understand the impact of therapeutic cannabinoids on the GI system of pediatric patients, we performed a systematic review and meta-analysis to assess the prevalence of various GI-related adverse events arising from cannabinoid usage within pediatric populations.MethodsSearches were conducted from OVID MEDLINE, EMBASE, CINAHL, Web of Science, and The Cochrane Library for study screening. The included studies were quantitatively assessed for GI adverse events including nausea, diarrhea, increased appetite, decreased appetite, weight gain, weight loss, constipation, abdominal pain, and unspecified events. The prevalence along with their relation towards diagnosis, type of cannabinoid, dosage, duration of treatment, and study type were also assessed.ResultsAmong a total of 1201 patients across 25 included studies, an overall prevalence of 33.91% GI adverse events was observed in patients. The statistical analysis of the pediatric population displayed no relation between therapeutic cannabinoid usage and GI adverse events, bearing a large heterogeneity (I2 = 91%, P < 0.01). Upon analysis based on study type, a significant difference was observed between prospective and retrospective studies in categories of all GI adverse events, diarrhea, and decreased appetite, with prospective studies displaying a higher prevalence in all three categories. Nausea symptoms showed a significant negative correlation with maximum dosage of cannabinoid used. In addition, diarrhea was found to have a higher prevalence in Dravet syndrome related to an ion channel gene mutation (SCN1A) compared to other epilepsy patients.ConclusionsWhile the meta-analysis did not identify any significant associations between therapeutic cannabinoid usage and GI adverse events, there remains the potential for interactions of cannabinoids on GI symptoms depending on dosage and underlying patient factors.Funding AgenciesFarncombe Family Digestive Health Research Institute

Genetic Diagnosis Spectrum and Multigenic Burden of Exome-Level Rare Variants in a Childhood Epilepsy Cohort.

Childhood epilepsy is a considerably heterogeneous neurological condition with a high worldwide incidence. Genetic diagnosis of childhood epilepsy provides the most accurate pathogenetic evidence; however, a large proportion of highly suspected cases remain undiagnosed. Accumulation of rare variants at the exome level as a multigenic burden contributing to childhood epilepsy should be further evaluated. In this retrospective analysis, exome-level sequencing was used to depict the mutation spectra of 294 childhood epilepsy patients from Shanghai Children’s Medical Center, Department of Neurology. Furthermore, variant information from exome sequencing data was analyzed apart from monogenic diagnostic purposes to elucidate the possible multigenic burden of rare variants related to epilepsy pathogenesis. Exome sequencing reached a diagnostic rate of 30.61% and identified six genes not currently listed in the epilepsy-associated gene list. A multigenic burden study revealed a three-fold possibility that deleterious missense mutations in ion channel and synaptic genes in the undiagnosed cohort may contribute to the genetic risk of childhood epilepsy, whereas variants in the gene categories of cell growth, metabolic, and regulatory function showed no significant difference. Our study provides a comprehensive overview of the genetic diagnosis of a Chinese childhood epilepsy cohort and provides novel insights into the genetic background of these patients. Harmful missense mutations in genes related to ion channels and synapses are most likely to produce a multigenic burden in childhood epilepsy.

The Linkage Phase of the Polymorphism KCNH2-K897T Influences the Electrophysiological Phenotype in hiPSC Models of LQT2.

While rare mutations in ion channel genes are primarily responsible for inherited cardiac arrhythmias, common genetic variants are also an important contributor to the clinical heterogeneity observed among mutation carriers. The common single nucleotide polymorphism (SNP) KCNH2-K897T is associated with QT interval duration, but its influence on the disease phenotype in patients with long QT syndrome type 2 (LQT2) remains unclear. Human induced pluripotent stem cells (hiPSCs), coupled with advances in gene editing technologies, are proving an invaluable tool for modeling cardiac genetic diseases and identifying variants responsible for variability in disease expressivity. In this study, we have used isogenic hiPSC-derived cardiomyocytes (hiPSC-CMs) to establish the functional consequences of having the KCNH2-K897T SNP in cis- or trans-orientation with LQT2-causing missense variants either within the pore-loop domain (KCNH2A561T/WT) or tail region (KCNH2N996I/WT) of the potassium ion channel, human ether-a-go-go-related gene (hERG). When KCNH2-K897T was on the same allele (cis) as the primary mutation, the hERG channel in hiPSC-CMs exhibited faster activation and deactivation kinetics compared to their trans-oriented counterparts. Consistent with this, hiPSC-CMs with KCNH2-K897T in cis orientation had longer action and field potential durations. Furthermore, there was an increased occurrence of arrhythmic events upon pharmacological blocking of hERG. Collectively, these results indicate that the common polymorphism KCNH2-K897T differs in its influence on LQT2-causing KCNH2 mutations depending on whether it is present in cis or trans. This study corroborates hiPSC-CMs as a powerful platform to investigate the modifying effects of common genetic variants on inherited cardiac arrhythmias and aids in unraveling their contribution to the variable expressivity of these diseases.

Abstract 13546: Putative Titin Mutations Associated With Both Long QT Syndrome and Left Ventricular Noncompaction

Introduction: Inherited long QT Syndrome (LQTS) is characterized by prolonged QTc intervals on electrocardiogram (EKG), ventricular arrhythmias and sudden death (SCD), and is caused by mutations in ion channel or ion-channel related genes. Inherited forms of dilated cardiomyopathy (DCM) and left ventricular noncompaction (LVNC), on the other hand, are caused by mutations in sarcomeric and structural genes including titin. Methods: Two unrelated families with histories of SCD presented to us for clinical evaluation of LQTS. Clinical genetic testing covering arrhythmia and cardiomyopathy genes was performed on each proband, with carrier testing on other family members. Results (Figure): The proband of family 1 had a strong family history of SCD, carried the clinical diagnosis of LQTS treated with propranolol, and had normal cardiac function by echocardiography. Following chemotherapy with adriamycin for breast cancer, evaluation showed a QTc of 514 ms on EKG, non-sustained VT on Holter, and LVNC with an LVEF=43% on cardiac MRI (cMRI). Genetic testing identified a likely pathogenic nonsense TTN variant (p.W18202*) along with a benign TTN polymorphism (p.E689K). Her clinically normal daughter did not carry the p.W18202* variant. The proband of family 2 had a strong family history of LQTS and SCD and was diagnosed with LQTS in her 20s after her mother suffered a cardiac arrest. Evaluation showed a QTc of 500 ms on EKG and biventricular LVNC with an LVEF=48% on cMRI. Genetic testing identified a likely pathogenic frameshift TTN variant (p.E18038Rfs*47). Three of her children carried the variant and had borderline or prolonged QTc intervals; one had hypertrabeculation on cMRI. Conclusion: We have identified two truncating TTN variants in close proximity to each other in unrelated families with overlapping LQTS/LVNC/DCM syndromes. Mutations in TTN may play a previously unappreciated role in the pathogenesis of inherited arrhythmia syndromes.

Abstract 12672: A New Genetic Model Organism for Primate-Specific Cardiac Function and Disease

Introduction: Due to differences in cardiac structure and function, it has become increasingly clear that many aspects of cardiovascular disease are not well modeled in mice. This has spurred a search for new model organisms with the practical advantages of mice but that more closely mimic human biology. This study examines mouse lemur (Microcebus species) - the world’s smallest, most prolific, and among the most abundant non-human primates - and the cheapest and easiest to maintain, as such a model. Methods: This study characterizes the normal cardiac anatomy and histology, and baseline values for heart rate, cholesterol, and cardiac waveform by ECG (a point-of-care blood assay and a portable 3-lead monitoring device were used to screen ~400 animals). It also describes the development of a whole genome and single cell RNA-sequencing and analysis pipeline for Microcebus murinus. Results: Transcriptomic analysis identified 6000 cardiac cells, including all major and many minor cardiac cell types, including several exceedingly rare cell types. The lipid profiles of these animals more closely resembled that of humans, with an average LDL level of 81 mg/dL, with several obese animals having values &gt;200. 20 naturally-occurring ECG variants were identified, all resembling known human ECG variants including 8 major cardiac arrhythmias. The screen uncovered the first cases of heart disease in lemurs. One is atrial fibrillation; Another is sick sinus syndrome (SSS), whose human familial form arises from mutations in ion channel genes, HCN4 or SCN5A. Both arrythmias show familial clustering, with the SSS pedigree exhibiting an autosomal dominant inheritance pattern. SNP/variant analysis revealed 30 million variants in the SSS animals, and ongoing work has narrowed these to just a handful of high impact, functional variants in SCN5A, suggesting that the underlying mouse lemur SSS disease gene and causative mutation are the same as in humans. Conclusions: The results establish the mouse lemur as the first systematic, high-throughput primate genetic model for cardiovascular physiology and disease, and reveal human-like cardiac cell types and diseases. The approach uncovered naturally-occurring cardiac diseases that have not been found in mice.

Aldosterone and Primary Aldosteronism: Star Performers in Hypertension Research

Aldosterone and Primary Aldosteronism: Star Performers in Hypertension Research

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development of new molecular technologies, new genes and new phenotypes, including progressive myopathies, have been recently discovered, markedly increasing the complexity in the field. In this regard, new advances in SMICs show a less conventional role of ion channels in muscle cell division, proliferation, differentiation, and survival. Hence, SMICs represent an expanding and exciting field. Here, we review current knowledge of SMICs, with a description of their clinical phenotypes, cellular and molecular pathomechanisms, and available treatments.

Phenotype/Genotype Relationship in Left Ventricular Noncompaction: Ion Channel Gene Mutations Are Associated With Preserved Left Ventricular Systolic Function and Biventricular Noncompaction: Phenotype/Genotype of Noncompaction

BackgroundFew data exist concerning genotype–phenotype relationships in left ventricular noncompaction (LVNC). Methods and ResultsFrom a multicenter French Registry, we report the genetic and clinical spectrum of 95 patients with LVNC, and their genotype–phenotype relationship. Among the 95 LVNC, 45 had at least 1 mutation, including 14 cases of mutation in ion channel genes. In a complementary analysis including 16 additional patients with ion channel gene mutations, for a total of 30 patients with ion channel gene mutation, we found that those patients had higher median LV ejection fraction (60% vs 40%; P < .001) and more biventricular noncompaction (53.1% vs 18.5%; P < .001) than the 81 other patients with LVNC. Among them, both the 19 patients with an HCN4 mutation and the 11 patients with an RYR2 mutation presented with a higher LV ejection fraction and more frequent biventricular noncompaction than the 81 patients with LVNC but with no mutation in the ion channel gene, but only patients with HCN4 mutation presented with a lower heart rate. ConclusionsIon channel gene mutations should be searched systematically in patients with LVNC associated with either bradycardia or biventricular noncompaction, particularly when LV systolic function is preserved. Identifying causative mutations is of utmost importance for genetic counselling of at-risk relatives of patients affected by LVNC.

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.