Mutations In Channel Genes Research Articles

Absence of Pathognomonic or Inflammatory Patterns in Cardiac Biopsies From Patients With Brugada Syndrome

Background— Brugada syndrome (BrS) is characterized by the presence of coved ST-segment elevations in the right precordial leads (so-called type I ECG) and additional clinical features. Caused by cardiac ion channel gene mutations, BrS may be associated with ventricular and atrial conduction disturbances as well as ventricular fibrillation. Recent studies have discussed whether BrS is merely a primary electric disorder or whether inflammatory or other histopathologic abnormalities in the right ventricle (RV) underlie the ECG phenotype. Methods and Results— We retrospectively analyzed BrS biopsy samples from 21 unrelated patients for histopathologic abnormalities (hypertrophy, fibrosis, inflammation, fatty tissue) together with the patients’ clinical, genetic, and imaging data. Eleven patients (52%) had normal RV imaging (by angiography, echocardiography, or cardiac MRI). Results of myocardial biopsies were normal in 3 patients (14%) and revealed mostly moderate abnormalities in the others. Four patients (19%) had predominant fatty tissue in the RV myocardium. Using immunohistochemistry and conventional tissue staining, we could not detect inflammatory tissue changes, an observation compatible with the clinical absence of signs for myocarditis. Conclusions— Imaging and histopathologic evaluation may detect moderate but uncharacteristic cardiac abnormalities in patients with BrS. None of the patients had arrhythmogenic RV cardiomyopathy or overt myocarditis. Only in a small subset did predominant histopathologic abnormalities in the biopsy samples of the RV outflow tract occur that could provide a link to the ECG phenotype. A variety of mechanisms, including genetic and structural RV alterations, may underlie the Brugada ECG phenotype.

Investigation of mutations associated with pyrethroid resistance in populations of the New World Screwworm fly, Cochliomyia hominivorax (Diptera: Calliphoridae)

Cochliomyia hominivorax larvae are known for their parasitic habit in living vertebrates, causing considerable economic losses to livestock industry. This ectoparasite has been controlled mainly by applying insecticides, but this method usually results in the selection of resistant individuals. The resistance mechanism known as knockdown resistance (kdr) is a generic term for amino acid substitutions in the sodium channel associated with pyrethroid resistance, and substitutions in residue 251 of the carboxylesterase E3 have been associated with organophosphate and pyrethroid hydrolysis. We looked for L1014F kdr and W251S mutations in the sodium channel and E3 genes, respectively, in C. hominivorax populations. Ten populations obtained from its current distribution were investigated using the polymerase chain reaction-restriction fragment length polymorphism technique. No mutant individuals were found for the kdr mutation. However, the W251S mutation was found in all populations investigated. Results from a bioassay with cypermethrin (a pyrethroid) indicated that the survival at the lowest concentration (Fisher exact test, P = 0.0003) and an intermediate concentration (P = 0.024) were associated with the W251S mutation. This correlation was not significant at the highest concentration tested (P = 0.221). We suggest that the W251S mutation in the C. hominivorax carboxylesterase E3 is also associated with pyrethroid hydrolysis. This information may contribute to the elaboration of improved management programs for this ectoparasite.

Molecular Pathology of Genetic Epilepsies Associated with GABAA Receptor Subunit Mutations

Mutations in ligand-gated ion channel genes associated with idiopathic generalized epilepsies have been reported in excitatory acetylcholine receptor alpha4 and beta2 subunit genes linked to autosomal dominant nocturnal frontal lobe epilepsy and in inhibitory GABA(A) receptor alpha1, beta3, gamma2, and delta subunit genes associated with childhood absence epilepsy, juvenile myoclonic epilepsy, pure febrile seizures, generalized epilepsy with febrile seizures plus, and generalized epilepsy with tonic-clonic seizures. Recent studies suggest that these mutations alter receptor function or biogenesis, including impaired receptor subunit messenger RNA stability, receptor subunit protein folding and stability, receptor assembly, and receptor trafficking.

Debate: Does genetic information in humans help us treat patients?

PRO: In the past decade, genotyping has started to help the neurologic practitioner treat patients with three types of epilepsy causing mutations, namely (1) SCN1A, a sodium channel gene mutated in Dravet's sporadic severe myoclonic epilepsy of infancy (SMEI and SMEB); (2) laforin (dual specificity protein phosphatase) and malin (ubiquitin E3 ligase) in Lafora progressive myoclonic epilepsy (PME); and (3) cystatin B in Unverricht-Lundborg type of PME. Laforin, malin, and cystatin B are non-ion channel gene mutations that cause PME. Genotyping ensures accurate diagnosis, helps treatment and genetic counseling, psychological and social help for patients and families, and directs families to organizations devoted to finding cures for specific epilepsy diseases. In SCN1A and cystatin B mutations, treatment with sodium channel blockers (phenytoin, carbamazepine, oxcarbazepine, lamotrigine) should be avoided. Because of early and correct diagnosis by genotyping of SCN1A mutations, the avoidance of sodium channel blockers, and aggressive treatment of prolonged convulsive status, there is hope that Dravet's syndrome may not be as severe as observed in all past reports. Genotyping also identifies nonsense mutations in Lafora PME. Nonsense mutations can be corrected by premature stop codon readthrough drugs such as gentamicin. The community practitioner together with epilepsy specialists in PME can work together and acquire gentamicin (Barton-Davis et al., 1999) for "compassionate use" in Lafora PME, a generalized lysosome multiorgan storage disorder that is invariably fatal. In Unverricht-Lundborg PME, new cohorts with genotyped cystatin B mutations have led to the chronic use of antioxidant N-acetylcysteine and combination valproate clobazam or clonazepam plus antimyoclonic drugs topiramate, zonisamide, piracetam, levetiracetam, or brivaracetam. These cohorts have minimal ataxia and no dementia, questioning whether the syndrome is truly progressive. In conclusion, not only is genotyping a prerequisite in the diagnosis of Dravet's syndrome and the progressive myoclonus epilepsies, but it also helps us choose the correct antiepileptic drugs to treat seizures in Dravet's syndrome and Unverricht-Lundborg PME. Genotyping also portends a brighter future, helping us to reassess the true course, severity, and progressive nature of Dravet's syndrome and Unverricht-Lundborg PME and helping us craft a future curative treatment for Dravet's syndrome and Lafora disease. Without the genotyping diagnosis of epilepsy causing mutations we are stuck with imprecise diagnosis and symptomatic treatment of seizures. CON: Genotyping of epilepsy may help to better understand the genetics of epilepsy, to establish an etiology in a patient with epilepsy, to provide genetic counseling, and to confirm a clinical diagnosis. However, critical analysis reveals that genotyping does not contribute to an improved treatment for the patients. In order to improve treatment, genotyping would have to (1) improve our ability to select the drug of choice for a given epilepsy or epileptic syndrome; (2) improve our ability to predict the individual risk of adverse reactions to certain drugs; (3) improve our ability to avoid unnecessary treatments or treatments that could aggravate seizures. Many example illustrate the lack of impact of genetic information on the treatment outcome: we do not treat Dravet syndrome more successfully since SCN1A testing became available; we do not treat Lafora disease more successfully since testing for laforin and malin became available; we do not need to know the genetic nature of Unverricht-Lundborg disease or test for the cystatin B mutation in order to select or avoid certain drugs; we do not treat Rett syndrome more successfully since MECP2 testing became available; we do not treat JME more successfully since we know its genetic origin; we do not treat autosomal dominant nocturnal frontal lobe epilepsy more successfully since we know its genetic origin and can test for its mutation. The clinical characteristics as well as the response to treatment of these epilepsy syndromes have been well established before genotyping became available. It can not be argued that genotyping is necessary for establishing a diagnosis or ensure accurate diagnosis. Since not all individuals with given syndromes have been shown to have the corresponding mutation, the clinical diagnosis must have been based on well-established clinical criteria. In addition, the presence or absence of the mutation in a given patient has never been shown to specifically predict the response to any form of treatment, positive or negative. Finally, the appropriate psychological and social help in a given patient will not depend on the identification of a mutation. This does not leave any role for genotyping in epilepsy for the sole reason of improving treatment of the patient. Claiming that the result of genotyping predicts optimal treatment in certain epilepsies is equivalent to stating that genotyping for diabetes has become available and that, based on this breakthrough, insulin can now be selected as the treatment of choice in those who test positive.

Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional Cardiac Sodium Channel

Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy and may contribute to perinatal and neonatal mortality, but the molecular basis of this risk and the relationship to genetic disorders presenting later in life is unclear. We studied the functional and pharmacological properties of a novel de novo cardiac sodium channel gene (SCN5A) mutation associated with an extremely severe perinatal presentation of long-QT syndrome in unrelated probands of different ethnicity. Two subjects exhibiting severe fetal and perinatal ventricular arrhythmias were screened for SCN5A mutations, and the functional properties of a novel missense mutation (G1631D) were determined by whole-cell patch clamp recording. In vitro electrophysiological studies revealed a profound defect in sodium channel function characterized by approximately 10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, and depolarized voltage dependence of activation and inactivation. Single-channel recordings demonstrated increased frequency of late openings, prolonged mean open time, and increased latency to first opening for the mutant. Subjects carrying this mutation responded clinically to the combination of mexiletine with propranolol and survived. Pharmacologically, the mutant exhibited 2-fold greater tonic and use-dependent mexiletine block than wild-type channels. The mutant also exhibited enhanced tonic (2.4-fold) and use-dependent block ( approximately 5-fold) by propranolol, and we observed additive effects of the 2 drugs on the mutant. Our study demonstrates the molecular basis for a malignant perinatal presentation of long-QT syndrome, illustrates novel functional and pharmacological properties of SCN5A-G1631D, which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting.

Les paralysies périodiques : nouveaux aspects physiopathologiques

Periodic paralyses are neuromuscular disorders characterized by attacks of muscle weakness coinciding with changes in blood potassium levels. They are thus classified as hypokalaemic, normokalaemic or hyperkalaemic. Most forms are genetic, with autosomal dominant inheritance. These diseases are channelopathies, i.e. caused by mutations in ion channel genes. The culprit genes encode muscle sodium, calcium and potassium channels. Mutations in calcium or potassium channels cause periodic paralyses of the same type (hypokalaemic periodic paralysis or Andersen-Tawil Syndrome). In contrast, distinct mutations in the gene encoding the sodium channel can cause the entire range of periodic paralysis (hypokalaemic, normokalaemic or hyperkalaemic). The physiological consequences of mutations have been studied with patch-clamp techniques and electromyography. Generally speaking, mutations alter the excitability cycle of the muscle membrane, resulting in a loss of function (paralysis). Electromyographic studies have demonstrated a good correlation between symptoms and physiological parameters, giving rise to a classification that can help orient the molecular diagnosis. Work on the genetics and pathophysiology of periodic paralyses has helped to improve the diagnosis and management of these syndromes.

Involvement of AT1 receptor in swelling-induced regulation of IKs current in guinea pig atrium

Distention of cardiac atria promotes atrial fibrillation (AF). Stretch or swelling of myocytes stimulates slow component of IK (IKs) - major repolarizing conductance in the heart. Upregulation of IKs was linked to pathogenesis of AF since gain-of-function mutations in IKs channel genes have been detected in hereditary form of AF. Moreover, stretch of cell membranes changes conformation of AT1 receptor and activates its downstream pathways.

Inheritance of pyrethroid resistance and a sodium channel gene mutation in the cattle tick Boophilus microplus

A substitution (Phe-->Ile) within the sodium channel gene sequence has been associated with pyrethroid resistance in Boophilus microplus. The aim of the present study was to analyze the inheritance of pyrethroid resistance and the mutant allele, on reciprocal crosses of a susceptible (SS) and a resistant (RR) strain. Bioassays and genotypes were determined to evaluate pyrethroid resistance. The resistance allele frequency of both parental strains were 100% and 2.27% for RR and SS, respectively. The reciprocal crosses show a predominance of the heterozygote genotype, in agreement with the significant decrease of the acaricide resistance to cypermethrin, deltamethrin, and flumethrin. However, the RS progeny showed a complete recessive survival (D (ML) = 0) for deltamethrin and flumethrin, suggesting a complete dominance of the susceptible allele and incomplete dominance for cypermethrin (D (ML) = 0.169). On the other hand, SR progeny showed a partially recessive survival for cypermethrin (D (ML) = 0.380), deltamethrin (D (ML) = 0.319), and flumethrin (D (ML) = 0.258), indicative of a partially dominant inheritance of the resistance. A possible maternal strain effect should be considered for practical purposes and prediction of acaricide resistance and further work needs to be done to elucidate the underlying inheritance of pyrethroid resistance and the sodium channel mutation in B. microplus.

Genes e epilepsia I: epilepsia e alterações genéticas

Epilepsy is a neurological disorder characterized by spontaneous and recurrent seizures with an estimated prevalence of 2-3 % in the world population. Epileptic seizures are the result of paroxystic and hypersynchronous electrical activity, preferentially in cortical areas, caused by panoply of structural and neurochemical dysfunctions. Recent advances in the field have focused on the molecular mechanisms involved in the epileptogenic process. In the present review, we describe the main genetic alterations associated to the process of epileptogenesis and discuss the new findings that are shedding light on the molecular substrates of monogenic idiopathic epilepsies (MIE) and on genetically complex epilepsies (GCE). Linkage and association studies have shown that mutations in ion channel genes are the main causes of MIE and of predisposition for GCE. Moreover, mutations in genes involved in neuronal migration, glycogen metabolism and respiratory chain are associated to other syndromes involving seizures. Therefore, different gene classes contribute to the epileptic trait. The identification of epilepsy-related gene families can help us understand the molecular mechanisms of neuronal hyperexcitability and recognize markers of early diagnosis as well as new treatments for these epilepsies.

Functional Effects of KCNE3 Mutation and Its Role in the Development of Brugada Syndrome

The Brugada Syndrome (BrS), an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in four different genes leading to a loss of function in sodium and calcium channel activity. Although the transient outward current (I(to)) is thought to play a prominent role in the expression of the syndrome, mutations in I(to)-related genes have not been identified as yet. One hundred and five probands with BrS were screened for ion channel gene mutations using single strand conformation polymorphism (SSCP) electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in one proband. The R99H mutation was found 4/4 phenotype positive and 0/3 phenotype-negative family members. Chinese hamster ovary (CHO)-K1 cells were co-transfected using wild-type (WT) or mutant KCNE3 and either WT KCND3 or KCNQ1. Whole-cell patch clamp studies were performed after 48 hours. Interactions between Kv4.3 and KCNE3 were analyzed in co-immunoprecipitation experiments in human atrial samples. Co-transfection of R99H-KCNE3 with KCNQ1 produced no alteration in current magnitude or kinetics. However, co-transfection of R99H KCNE3 with KCND3 resulted in a significant increase in the I(to) intensity compared to WT KCNE3+KCND3. Using tissues isolated from left atrial appendages of human hearts, we also demonstrate that K(v)4.3 and KCNE3 can be co-immunoprecipitated. These results provide definitive evidence for a functional role of KCNE3 in the modulation of I(to) in the human heart and suggest that mutations in KCNE3 can underlie the development of BrS.

Muscle Channelopathies

In recent years the term CHANNELOPATHY has been adopted to describe neurological disorders caused by mutations in different ion channel genes. Myopathic channelopathies include two main groups: nondystrophic myotonias and periodic paralyses. This article reviews the clinical features, diagnostic approach, molecular causes, and management of patients with nondystrophic myotonias and periodic paralyses.

Mutation analysis of candidate genes SCN1B, KCND3 and ANK2 in patients with clinical diagnosis of Long QT syndrome

The long QT syndrome (LQTS) is a monogenic disorder characterized by prolongation of the QT interval on electrocardiogram and syncope or sudden death caused by polymorphic ventricular tachycardia (torsades de pointes). In general, mutations in cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2) have been identified as a cause for LQTS. About 50-60 % of LQTS patients have an identifiable LQTS causing mutation in one of mentioned genes. In a group of 12 LQTS patients with no identified mutations in these genes we have tested a hypothesis that other candidate genes could be involved in LQTS pathophysiology. SCN1B and KCND3 genes encode ion channel proteins, ANK2 gene encodes cytoskeletal protein interacting with ion channels. To screen coding regions of genes SCN1B, KCND3, and 10 exons of ANK2 following methods were used: PCR, SSCP, and DNA sequencing. Five polymorphisms were found in screened candidate genes, 2 polymorphisms in KCND3 and 3 in SCN1B. None of found polymorphisms has coding effect nor is located close to splice sites or has any similarity to known splicing enhancer motifs. Polymorphism G246T in SCN1B is a novel one. No mutation directly causing LQTS was found. Molecular mechanism of LQTS genesis in these patients remains unclear.

Characterization of the M918T sodium channel gene mutation associated with strong resistance to pyrethroid insecticides in the peach-potato aphid, Myzus persicae (Sulzer)

Recent advances in the characterisation of insect sodium channel gene sequences have identified a small number of point mutations within the channel protein that are implicated in conferring target-site resistance to pyrethroid insecticides (so-called knockdown resistance or kdr). The L1014F (leucine-to-phenylalanine) mutation located in the centre of segment 6 of the domain II region (IIS6) of the sodium channel (the so-called kdr trait) has been detected in the peach-potato aphid, Myzus persicae (Sulzer), and is considered to be the primary cause of pyrethroid resistance in this species. Here we report on the characterisation of a second mutation, M918T (methione-to-threonine), within the nearby IIS4-S5 intracellular linker (the so-called super-kdr trait) in a field clone also possessing L1014F, with both mutations present in heterozygous form. The resistance phenotype of M. persicae clones possessing various combinations of L1014F and M918T to a wide range of pyrethroids (both Type I and II) was assessed in leaf-dip bioassays and to lambda-cyhalothrin applied at up to ten times the recommended field rate as foliar sprays to aphids feeding on whole plants. Bioassay results demonstrated that presence of both mutations was associated with extreme resistance to all the pyrethroids tested relative to aphids lacking the mutations. Furthermore, this resistance well exceeded that shown by aphids that were homozygous for L1014F but lacking M918T. However, pre-treatment with piperonyl butoxide in the leaf-dip bioassays failed to suppress pyrethroid resistance in aphids carrying one or both of the mutations. The relevance of these findings for monitoring and managing pyrethroid resistance in M. persicae populations in the field is discussed.

Cardiac potassium channel dysfunction in sudden infant death syndrome

Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5–10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wild-type channels (KCNH2 variants V279M, R885C, and S1040G). When co-expressed with WT-HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (IKr) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pause-dependent early afterdepolarizations. By contrast, KCNQ1-I274V causes a gain-of-function in IKs characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous I274V-IKs incorporated into the Luo–Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with SIDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome.

A KCNE2 mutation in a patient with cardiac arrhythmia induced by auditory stimuli and serum electrolyte imbalance

Auditory stimulus-induced long QT syndrome (LQTS) is almost exclusively linked to mutations in the hERG potassium channel, which generates the I Kr ventricular repolarization current. Here, a young woman with prior episodes of auditory stimulus-induced syncope presented with LQTS and ventricular fibrillation (VF) with hypomagnesaemia and hypocalcaemia after completing a marathon, followed by subsequent VF with hypokalaemia. The patient was found to harbour a KCNE2 gene mutation encoding a T10M amino acid substitution in MiRP1, an ancillary subunit that co-assembles with and functionally modulates hERG. Other family members with the mutation were asymptomatic, and the proband had no mutations in hERG or other LQTS-linked cardiac ion channel genes. The T10M mutation was absent from 578 unrelated, ethnically matched control chromosomes analysed here and was previously described only once-in an LQTS patient-but not functionally characterized. T10M-MiRP1-hERG currents were assessed using whole-cell voltage clamp of transfected Chinese Hamster ovary cells. T10M-MiRP1-hERG channels showed <or=80% reduced tail current, left-shifted steady-state inactivation, and 50% slower recovery from inactivation when compared with wild-type channels, with mixed wild-type/T10M channels displaying an intermediate phenotype. Lowering bath K+ concentration reduced wild-type and T10M currents equivalently. Data suggest a mechanism for reduced penetrance, inherited arrhythmia in which baseline I Kr current reduction by the T10M mutation is exacerbated by superimposition of arrhythmogenic substrates such as auditory stimuli, or electrolyte disturbances that reduce I Kr (hypokalaemia) or otherwise lower the ventricular threshold for fibrillation (hypomagnesaemia and hypocalcaemia). This first example of a MiRP1 mutation associated with auditory stimulus-induced arrhythmia is supportive of the hypothesis that MiRP1 regulates hERG in the human heart.

ATP-sensitive K+ channels and disease: from molecule to malady

This essay is based on a lecture given to the American Physiological Society in honor of Walter B. Cannon, an advocate of homeostasis. It focuses on the role of the ATP-sensitive potassium K+ (KATP) channel in glucose homeostasis and, in particular, on its role in insulin secretion from pancreatic β-cells. The β-cell KATP channel comprises pore-forming Kir6.2 and regulatory SUR1 subunits, and mutations in either type of subunit can result in too little or too much insulin release. Here, I review the latest information on the relationship between KATP channel structure and function, and consider how mutations in the KATP channel genes lead to neonatal diabetes or congenital hyperinsulinism.

Function and Dysfunction of CNG Channels: Insights from Channelopathies and Mouse Models

Channels directly gated by cyclic nucleotides (CNG channels) are important cellular switches that mediate influx of Na+ and Ca2+ in response to increases in the intracellular concentration of cAMP and cGMP. In photoreceptors and olfactory receptor neurons, these channels serve as final targets for cGMP and cAMP signaling pathways that are initiated by the absorption of photons and the binding of odorants, respectively. CNG channels have been also found in other types of neurons and in non-excitable cells. However, in most of these cells, the physiological role of CNG channels has yet to be determined. CNG channels have a complex heteromeric structure. The properties of individual subunits that assemble in specific stoichiometries to the native channels have been extensively investigated in heterologous expression systems. Recently, mutations in human CNG channel genes leading to inherited diseases (so-called channelopathies) have been functionally characterized. Moreover, mouse knockout models were generated to define the role of CNG channel proteins in vivo. In this review, we will summarize recent insights into the physiological and pathophysiological role of CNG channel proteins that have emerged from genetic studies in mice and humans.

The Perfect Storm

See related articles, pages 1039–1048 and 1049–1057 Primary electrical diseases of the heart such as the Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Brugada Syndrome (BrS), and Catecholaminergic polymorphic ventricular tachycardia (CPVT) are inherited monogenic disorders caused by mutations in ion channel genes (ie, channelopathies), calcium handling proteins, or related molecules that occur in the absence of overt structural abnormalities.1 Because these disorders are typically associated with a high incidence of ventricular tachyarrhythmias and sudden cardiac death (SCD), they are the subject of intense investigation. Although collectively, monogenic diseases underlie a minority of SCD cases in the general population, elucidation of the underlying mechanisms by which they promote electrical instability has provided a wealth of knowledge regarding the role of ion channel dysfunction in electrical remodeling and arrhythmogenesis at multiple levels of integration, linking single amino acid mutations in ion channel genes to electrical dysfunction at the intact cell, organ, and system levels. In recent years, numerous investigations have focused on mechanisms by which altered ion channel function and action potential properties can promote arrhythmias at the multi-cellular network level in various animal models of LQTS, SQTS, and BrS.2 In this issue of Circulation Research , Cerrone et al3 provide a strong mechanistic link between a known CPVT causing mutation and electrical instability arising from the His-Purkinje network of the intact heart in a tour de force study using high-resolution optical mapping, cellular electrophysiological measurements, a variety of pharmacological tools, and numerical simulations. CPVT is a heritable disorder that presents clinically as exercise- or stress- induced ventricular arrhythmias, syncope, or SCD.1 Electrocardiographically, patients with CPVT exhibit polymorphic VT (PVT), bidirectional VT with an alternating QRS axis (Bi-VT), and ventricular fibrillation (VF). Several mutations in the cardiac Ryanodine Receptor (RyR2) and Calsequestrin (CSQ) have been …

The state of the art in the genetic analysis of the epilepsies

Genetic influences as causal factors in the epilepsies continue to be vigorously investigated, and we review several important studies of genes reported in 2006. To date, mutations in ion channel and neuroreceptor component genes have been reported in the small fraction of cases with clear Mendelian inheritance. These findings confirm that the so-called "channelopathies" are generally inherited as monogenic disorders. At the same time, the literature in common epilepsies abounds with reports of associations and reports of nonreplication of those association studies, primarily with channel genes. These contradictory reports can mostly be explained by confounding factors unique to genetic studies. The methodology of genetic studies and their common biases and confounding factors are also explained in this review. Amid the controversy, steady progress is being made on the epilepsies of complex inheritance, which represent the most common idiopathic epilepsy. Recent discoveries show that genes influencing the developmental assembly of neural circuits and neuronal metabolism may play a more prominent role in the common epilepsies than genes affecting membrane excitability and synaptic transmission.

Postmortem molecular analysis of KCNQ1 and SCN5A genes in sudden unexplained death in young Australians

The cause of sudden death in young people remains unknown in up to 50% of postmortem cases. Mutations in the ion channel genes are known to cause primary arrhythmogenic disorders such as long QT and Brugada syndromes, which can present with sudden cardiac death and a negative autopsy. In this study, 59 sudden unexplained deaths occurring in Australians aged ≤ 35 years with a negative autopsy, from 1994–2002, were studied. Genomic DNA was extracted from paraffin-embedded tissues. Genetic analysis of the KCNQ1 and SCN5A genes was performed using denaturing high-performance liquid chromatography and direct DNA sequencing. Nine DNA sequence variants were identified in the KCNQ1 gene and 9 sequence variants were identified in the SCN5A gene. In total, 23 out of 59 cases were found to have at least one DNA variant in KCNQ1 or SCN5A, of which one, H558R in the SCN5A gene, caused an amino acid substitution. None of the DNA variants were determined to be disease causing as they were also identified in control populations. In conclusion, no disease-causing mutations were found in the KCNQ1 or SCN5A genes in this cohort. A more selective screening approach, including only individuals with a clinical or family history of arrhythmogenic disorders, may yield greater success in identifying disease-causing mutations in cohorts of young individuals who have died suddenly.