Potassium Channel Mutations Research Articles

IMPACT OF POTASSIUM CHANNEL GENE MUTATIONS ON OCCURRENCE OF LONE ATRIAL FIBRILLATION

Background: Mutations in multiple genes have been implicated in familial atrial ibrillation (AF). KCNQ1 was the irst disease gene identiied for familial AF, however, some recent reports showed that potassium channel mutations are not a major cause of AF in the general population. We sought to determine the frequency of potassium channel gene mutations in patients with lone AF and characterized the electrophysiological properties of the detected mutation.

Potassium-channel mutations and cardiac arrhythmias—diagnosis and therapy

The coordinated generation and propagation of action potentials within cardiomyocytes creates the intrinsic electrical stimuli that are responsible for maintaining the electromechanical pump function of the human heart. The synchronous opening and closing of cardiac Na(+), Ca(2+), and K(+) channels corresponds with the activation and inactivation of inward depolarizing (Na(+) and Ca(2+)) and outward repolarizing (K(+)) currents that underlie the various phases of the cardiac action potential (resting, depolarization, plateau, and repolarization). Inherited mutations in pore-forming α subunits and accessory β subunits of cardiac K(+) channels can perturb the atrial and ventricular action potential and cause various cardiac arrhythmia syndromes, including long QT syndrome, short QT syndrome, Brugada syndrome, and familial atrial fibrillation. In this Review, we summarize the current understanding of the molecular and cellular mechanisms that underlie K(+)-channel-mediated arrhythmia syndromes. We also describe translational advances that have led to the emerging role of genetic testing and genotype-specific therapy in the diagnosis and clinical management of individuals who harbor pathogenic mutations in genes that encode α or β subunits of cardiac K(+) channels.

Novel Insights into the Pathomechanisms of Skeletal Muscle Channelopathies

The nondystrophic myotonias and primary periodic paralyses are an important group of genetic muscle diseases characterized by dysfunction of ion channels that regulate membrane excitability. Clinical manifestations vary and include myotonia, hyperkalemic and hypokalemic periodic paralysis, progressive myopathy, and cardiac arrhythmias. The severity of myotonia ranges from severe neonatal presentation causing respiratory compromise through to mild later-onset disease. It remains unclear why the frequency of attacks of paralysis varies greatly or why many patients develop a severe permanent fixed myopathy. Recent detailed characterizations of human genetic mutations in voltage-gated muscle sodium (gene: SCN4A), chloride (gene: CLCN1), calcium (gene: CACNA1S), and inward rectifier potassium (genes: KCNJ2, KCNJ18) channels have resulted in new insights into disease mechanisms, clinical phenotypic variation, and therapeutic options.

Familial Atrial Fibrillation Mutation KCNQ1-S140G Exhibits Enhanced Sensitivity to Block by the IKs Selective Inhibitor HMR-1556

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia. The contribution of genetic factors to AF susceptibility has been emphasized by the discovery of mutations that enhance outward potassium current, predicted to shorten atrial action potential duration and predispose to re-entrant arrhythmia mechanisms. Understanding the genetic basis for familial AF can inspire new ideas regarding treatment of this common arrhythmia. We hypothesized that potassium channel mutations predisposing to AF may have distinct pharmacological properties from wild-type channels.

Congenital hyperinsulinism: current trends in diagnosis and therapy

Congenital hyperinsulinism (HI) is an inappropriate insulin secretion by the pancreatic β-cells secondary to various genetic disorders. The incidence is estimated at 1/50, 000 live births, but it may be as high as 1/2, 500 in countries with substantial consanguinity. Recurrent episodes of hyperinsulinemic hypoglycemia may expose to high risk of brain damage. Hypoglycemias are diagnosed because of seizures, a faint, or any other neurological symptom, in the neonatal period or later, usually within the first two years of life. After the neonatal period, the patient can present the typical clinical features of a hypoglycemia: pallor, sweat and tachycardia. HI is a heterogeneous disorder with two main clinically indistinguishable histopathological lesions: diffuse and focal. Atypical lesions are under characterization. Recessive ABCC8 mutations (encoding SUR1, subunit of a potassium channel) and, more rarely, recessive KCNJ11 (encoding Kir6.2, subunit of the same potassium channel) mutations, are responsible for most severe diazoxide-unresponsive HI. Focal HI, also diazoxide-unresponsive, is due to the combination of a paternally-inherited ABCC8 or KCNJ11 mutation and a paternal isodisomy of the 11p15 region, which is specific to the islets cells within the focal lesion. Genetics and 18F-fluoro-L-DOPA positron emission tomography (PET) help to diagnose diffuse or focal forms of HI. Hypoglycemias must be rapidly and intensively treated to prevent severe and irreversible brain damage. This includes a glucose load and/or a glucagon injection, at the time of hypoglycemia, to correct it. Then a treatment to prevent the recurrence of hypoglycemia must be set, which may include frequent and glucose-enriched feeding, diazoxide and octreotide. When medical and dietary therapies are ineffective, or when a focal HI is suspected, surgical treatment is required. Focal HI may be definitively cured when the partial pancreatectomy removes the whole lesion. By contrast, the long-term outcome of diffuse HI after subtotal pancreatectomy is characterized by a high risk of diabetes, but the time of its onset is hardly predictable.

Paroxysmal dyskinesias

Paroxysmal movement disorders are a relatively rare and heterogenous group of conditions manifesting as episodic dyskinesia lasting a brief duration. Three forms are clearly recognized, namely, paroxysmal kinesigenic (PKD), nonkinisegenic (PNKD), and exercise induced (PED). There have been major advances in the understanding of the pathophysiological mechanisms and the genetics of these disorders, leading to better clinical definitions based on genotype-phenotype correlations in the familial idiopathic forms. PKD is genetically heterogenous, but there is linkage to chromosome 16 in a number of families. PNKD is due to mutations of the MR-1 gene. PED is genetically heterogenous, but a number of familial and sporadic cases may be due to GLUT-1 gene mutations. The GLUT1 gene-related form of PED may respond to a ketogenic diet. Potassium and calcium channel mutations underlie the 2 main forms of episodic ataxia (EA1 and EA2), whereas benign torticollis of infancy may also be a calcium channel disorder.

Cardiac abnormalities in children with congenital hyperinsulinism [CHI

Congenital hyperinsulinism of Infancy (CHI) can be associated with cardiac problems such as septal hypertrophy and reversible hypertrophic cardiomyopathy1 2 however, the prevalence and range of cardiac abnormalities in CHI...

Double-Trouble Mutation

Potassium channel mutations drive both cell growth and hormone production in an adrenal tumor that causes severe hypertension.

K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.

Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na(+)) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca(2+)) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na(+) conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K(+) channel selectivity in constitutive cell proliferation and hormone production.

Genetic Study of Ischemia-Induced Ventricular Arrhythmia Associated with Potassium Channels

Objective: Recent research shows that sodium channel gene mutation is one of the disease-causing gene in ischemia-induced ventricular arrhythmia. In this study, in order to reveal the relationship between ischemia-induced ventricular arrhythmia and potassium channel mutation. Methods: 23 patients with ischemia-induced ventricular arrhythmia were selected. 5ML peripheral blood was taken and DNA extracted. 11 candidate genes including HERG, KCNQ1, KCNE1, KCNE2, KCNJ2, KCNJ3, KCNJ8, KCNJ11, KCNJ12, KCND3 and KCNA5 were screened with direct sequencing methods. Results: 10 Potassium channel SNP have been found. The G216G is a novel SNP, which shows a change from T base to C base at the position of 1353 on the third exon of KCNJ12 gene. The SNP distribution from KCNJ12-Q192H, KCNJ12-P156L, HERG-I489I, KV1.5-P513P, Kir2.1-L382L, Kir6.2-V337I, KCNQ1-P448R and KCNQ1-S546S are similar with reported. The SNP of F513F is at the position of 1545 C base substitution T base on the seventh exon of the HERG gene. 5 patients have been found the SNP of F513F while 44 in the control group. Chi-square test shows that there is a difference in the incidence of the F513F SNP between the two groups. Conclusion: No potassium channel gene mutation has been found. A novel SNP of KCNJ12-G216G was discovered in Chinese people. The SNP of HERG-F513F might be a predisposing factor in ischemia-induced ventricular arrhythmia.

Potassium channelopathies of epilepsy

SummaryThe potassium channel family represents a large group with diverse functional roles. Not surprisingly, the list of potassium channelopathies contributing to human epilepsy has greatly expanded. The focus of this chapter will be the causative role in epilepsy of mutations in potassium channels and associated regulatory proteins. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado‐Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books).

Drug-Induced Arrhythmia

Prolongation of the QTc interval has been associated with proarrhythmia resulting from a potentially fatal form of polymorphic ventricular tachycardia called torsades de pointes (TdP). Genetic forms of the long-QT syndrome (LQTS) associated with high arrhythmic risk have been causally related to mutations in ion channels responsible for the cardiac action potential; genetic factors associated with milder degrees of QTc prolongation and arrhythmic risk have also been described. Acquired forms of QTc prolongation and proarrhythmia, particularly related to drug therapy, are frequently related to drug effects on the same ion channels involved in genetic forms of LQTS. As is true for genetic forms of LQTS, there is a wide spectrum of potential drug effects on the QTc interval ranging from trivial to potentially lethal. Drug-induced QTc prolongation is a complicated phenomenon related not just to the properties or dose of a particular drug but also to drug-drug interactions and a variety of patient factors, including age, gender, the presence and severity of underlying heart disease, and genetic predisposition. Additionally, drug effects on other ion channels, including blockade of sodium channels (causing prolongation of the QRS interval rather than the QTc interval), are an important cause of drug-induced proarrhythmia. The purpose of this review is to summarize the available data related to acquired forms of LQTS, with particular focus on drug-related LQTS and proarrhythmia. A brief summary is presented here of genetic LQTS because the relevant genes and proteins form the basis for an understanding of the causes of acquired LQTS, and in any given patient, the QTc is determined by genetic, substrate, and environmental factors. Emphasis is placed on practical strategies for clinicians, with the goal of minimizing the risk of dangerous proarrhythmia related to the use of both cardiac and noncardiac drugs with the potential for QTc prolongation. Genetic …

Familial neonatal seizures with intellectual disability caused by a microduplication of chromosome 2q24.3

A family with dominantly inherited neonatal seizures and intellectual disability was atypical for neonatal and infantile seizure syndromes associated with potassium (KCNQ2 and KCNQ3) and sodium (SCN2A) channel mutations. Microsatellite markers linked to KCNQ2, KCNQ3, and SCN2A were examined to exclude candidate locations, but instead revealed a duplication detected by observation of three alleles for two markers flanking SCN2A. Characterization revealed a 1.57 Mb duplication at 2q24.3 containing eight genes including SCN2A, SCN3A, and the 3¢ end of SCN1A. The duplication was partially inverted and inserted within or near SCN1A, probably affecting the expression levels of associated genes, including sodium channels. Rare or unique microchromosomal copy number mutations might underlie familial epilepsies that do not fit within the clinical criteria for the established syndromes.

The KCNQ5 potassium channel mediates a component of the afterhyperpolarization current in mouse hippocampus

Mutations in KCNQ2 and KCNQ3 voltage-gated potassium channels lead to neonatal epilepsy as a consequence of their key role in regulating neuronal excitability. Previous studies in the brain have focused primarily on these KCNQ family members, which contribute to M-currents and afterhyperpolarization conductances in multiple brain areas. In contrast, the function of KCNQ5 (Kv7.5), which also displays widespread expression in the brain, is entirely unknown. Here, we developed mice that carry a dominant negative mutation in the KCNQ5 pore to probe whether it has a similar function as other KCNQ channels. This mutation renders KCNQ5(dn)-containing homomeric and heteromeric channels nonfunctional. We find that Kcnq5(dn/dn) mice are viable and have normal brain morphology. Furthermore, expression and neuronal localization of KCNQ2 and KCNQ3 subunits are unchanged. However, in the CA3 area of hippocampus, a region that highly expresses KCNQ5 channels, the medium and slow afterhyperpolarization currents are significantly reduced. In contrast, neither current is affected in the CA1 area of the hippocampus, a region with low KCNQ5 expression. Our results demonstrate that KCNQ5 channels contribute to the afterhyperpolarization currents in hippocampus in a cell type-specific manner.

Neurogenetics: from hypokalemic periodic paralysis as an arginine deficiency to the influence of mitochondrial DNA haplogroups on therapeutic response in migraine

Over the last 20 years neurogenetics has become more and more important and clinically relevant with regard to a definite diagnosis of certain syndromes, an understanding of the underlying pathophysiology and the development of new therapeutic principles. Hot spots in this field are channelopathies. More and more neurological disorders, ranging from familial hemiplegic migraine and episodic ataxias to muscle disorders, have been identified as channelopathies. The first article in this month’s Journal Club deals with hypokalemic periodic paralysis and the underlying voltage sensory charge loss that evidently causes the symptoms. One may therefore also call hypokalemic periodic paralysis an arginine deficiency syndrome or an argininopathy. The background will be explained below. In the second article—published in The New England Journal of Medicine—a new syndrome is described: the EAST syndrome characterised by epilepsy, ataxia, sensorineural deafness and tubulopathy, which is caused by a potassium channel mutation. This mutation has consequences for the functioning of several organs. As pointed out in the accompanying Editorial, this finding bridges the gap between medical disciplines whose general separation has been a strange tradition for decades. In the third article, the influence of mitochondrial DNA haplogroups on the therapeutic response to riboflavin in migraineurs is evaluated. This is a very interesting approach by which the response of certain groups of patients to certain drugs might be predicted in the future, allowing a more specific treatment. Finally, the author of the Journal Club recommends a so-called an occasional paper published recently in Brain on an acquired personality disorder in US presidents and UK prime ministers: hubris syndrome. Frankly speaking, this syndrome might have more devastating consequences for our well-being than many neurological disorders.

Re-evaluating the efficacy of β-adrenergic agonists and antagonists in long QT-3 syndrome through computational modelling

Long QT syndrome (LQTS) is a heterogeneous collection of inherited cardiac ion channelopathies characterized by a prolonged electrocardiogram QT interval and increased risk of sudden cardiac death. Beta-adrenergic blockers are the mainstay of treatment for LQTS. While their efficacy has been demonstrated in LQTS patients harbouring potassium channel mutations, studies of beta-blockers in subtype 3 (LQT3), which is caused by sodium channel mutations, have produced ambiguous results. In this modelling study, we explore the effects of beta-adrenergic drugs on the LQT3 phenotype. In order to investigate the effects of beta-adrenergic activity and to identify sources of ambiguity in earlier studies, we developed a computational model incorporating the effects of beta-agonists and beta-blockers into an LQT3 mutant guinea pig ventricular myocyte model. Beta-activation suppressed two arrhythmogenic phenomena, transmural dispersion of repolarization and early after depolarizations, in a dose-dependent manner. However, the ability of beta-activation to prevent cardiac conduction block was pacing-rate-dependent. Low-dose beta-blockade by propranolol reversed the beneficial effects of beta-activation, while high dose (which has off-target sodium channel effects) decreased arrhythmia susceptibility. These results demonstrate that beta-activation may be protective in LQT3 and help to reconcile seemingly conflicting results from different experimental models. They also highlight the need for well-controlled clinical investigations re-evaluating the use of beta-blockers in LQT3 patients.

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.

Homozygous Missense N629D hERG (KCNH2) Potassium Channel Mutation Causes Developmental Defects in the Right Ventricle and Its Outflow Tract and Embryonic Lethality

Loss-of-function mutations in the human ERG1 potassium channel (hERG1) frequently underlie the long QT2 (LQT2) syndrome. The role of the ERG potassium channel in cardiac development was elaborated in an in vivo model of a homozygous, loss-of-function LQT2 syndrome mutation. The hERG N629D mutation was introduced into the orthologous mouse gene, mERG, by homologous recombination in mouse embryonic stem cells. Intact homozygous embryos showed abrupt cessation of the heart beat. N629D/N629D embryos die in utero by embryonic day 11.5. Their developmental defects include altered looping architecture, poorly developed bulbus cordis, and distorted aortic sac and branchial arches. N629D/N629D myocytes from embryonic day 9.5 embryos manifested complete loss of I(Kr) function, depolarized resting potential, prolonged action potential duration (LQT), failure to repolarize, and propensity to oscillatory arrhythmias. N629D/N629D myocytes manifest calcium oscillations and increased sarcoplasmic reticulum Ca(+2) content. Although the N629D/N629D protein is synthesized, it is mainly located intracellularly, whereas +/+ mERG protein is mainly in plasmalemma. N629D/N629D embryos show robust apoptosis in craniofacial regions, particularly in the first branchial arch and, to a lesser extent, in the cardiac outflow tract. Because deletion of Hand2 produces apoptosis, in similar regions and with a similar final developmental phenotype, Hand2 expression was evaluated. Robust decrease in Hand2 expression was observed in the secondary heart field in N629D/N629D embryos. In conclusion, loss of I(Kr) function in N629D/N629D cardiovascular system leads to defects in cardiac ontogeny in the first branchial arch, outflow tract, and the right ventricle.

Congenital Long-QT Syndromes

The congenital long-QT syndromes (LQTS) were initially described approximately 50 years ago.1–3 The principal events are syncope, seizures, and ventricular tachycardia, characteristically torsade de pointes. Most often, this arrhythmia is self terminating, producing a syncopal episode; however, LQTS is responsible for a significant proportion of sudden cardiac deaths (SCDs) in young people without structural heart disease, estimated to have an incidence of approximately 1 in 2500 and causing thousands of deaths annually.4–6 Characteristic ECG signs of LQTS include QT-interval prolongation and T-wave abnormalities. The heart rate–corrected QT interval (QTc) can range from 370 to >700 ms, clearly overlapping that of normal individuals, and a single ECG may not manifest the stereotypical features.7–9 Some patients have a normal or borderline QTc at rest but prolongation with exertion or β-adrenergic stimulation. Provocative testing with exercise or catecholamine infusion may improve the sensitivity of LQTS clinical detection.9–11 The inciting triggers are somewhat mutation-specific. Patients with potassium channel mutations typically have episodes during physical or emotional stress, whereas those with sodium channel defects have more events with bradycardia and during sleep.12–15 Symptoms, including syncope or SCD, can manifest anytime from the neonatal period to adulthood. Because risk stratification is still being refined, it is often recommended that most LQTS patients be treated with β-adrenergic blocking medications, but a diagnostic challenge is deciding who needs more specific or aggressive therapies. Interventions for LQTS include implantation of a permanent pacemaker or implantable cardioverter defibrillator (ICD), as well as consideration of left cardiac sympathetic denervation. If interventional therapy is warranted, what procedures are right for which patients, and when is the optimal time to intervene?16 The competing risks of the disease versus potential complications from the procedures or devices often increase the complexity of the clinical decision-making rationale. Articles p 2184 …

Evolutionary analyses of KCNQ1 and HERG voltage-gated potassium channel sequences reveal location-specific susceptibility and augmented chemical severities of arrhythmogenic mutations

BackgroundMutations in HERG and KCNQ1 potassium channels have been associated with Long QT syndrome and atrial fibrillation, and more recently with sudden infant death syndrome and sudden unexplained death. In other proteins, disease-associated amino acid mutations have been analyzed according to the chemical severity of the changes and the locations of the altered amino acids according to their conservation over metazoan evolution. Here, we present the first such analysis of arrhythmia-associated mutations (AAMs) in the HERG and KCNQ1 potassium channels.ResultsUsing evolutionary analyses, AAMs in HERG and KCNQ1 were preferentially found at evolutionarily conserved sites and unevenly distributed among functionally conserved domains. Non-synonymous single nucleotide polymorphisms (nsSNPs) are under-represented at evolutionarily conserved sites in HERG, but distribute randomly in KCNQ1. AAMs are chemically more severe, according to Grantham's Scale, than changes observed in evolution and their severity correlates with the expected chemical severity of the involved codon. Expected chemical severity of a given amino acid also correlates with its relative contribution to arrhythmias. At evolutionarily variable sites, the chemical severity of the changes is also correlated with the expected chemical severity of the involved codon.ConclusionUnlike nsSNPs, AAMs preferentially locate to evolutionarily conserved, and functionally important, sites and regions within HERG and KCNQ1, and are chemically more severe than changes which occur in evolution. Expected chemical severity may contribute to the overrepresentation of certain residues in AAMs, as well as to evolutionary change.