Potassium Channel Mutations Research Articles

Editorial: Adrenal Cortex: From Physiology to Disease

Editorial: Adrenal Cortex: From Physiology to Disease

Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery.

In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets.

Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes.

Aims/hypothesisThe finding that patients with diabetes due to potassium channel mutations can transfer from insulin to sulfonylureas has revolutionised the management of patients with permanent neonatal diabetes. The extent to which the in vitro characteristics of the mutation can predict a successful transfer is not known. Our aim was to identify factors associated with successful transfer from insulin to sulfonylureas in patients with permanent neonatal diabetes due to mutations in KCNJ11 (which encodes the inwardly rectifying potassium channel Kir6.2).MethodsWe retrospectively analysed clinical data on 127 patients with neonatal diabetes due to KCNJ11 mutations who attempted to transfer to sulfonylureas. We considered transfer successful when patients completely discontinued insulin whilst on sulfonylureas. All unsuccessful transfers received ≥0.8 mg kg−1 day−1 glibenclamide (or the equivalent) for >4 weeks. The in vitro response of mutant Kir6.2/SUR1 channels to tolbutamide was assessed in Xenopus oocytes. For some specific mutations, not all individuals carrying the mutation were able to transfer successfully; we therefore investigated which clinical features could predict a successful transfer.ResultsIn all, 112 out of 127 (88%) patients successfully transferred to sulfonylureas from insulin with an improvement in HbA1c from 8.2% (66 mmol/mol) on insulin, to 5.9% (41 mmol/mol) on sulphonylureas (p = 0.001). The in vitro response of the mutation to tolbutamide determined the likelihood of transfer: the extent of tolbutamide block was <63% for the p.C166Y, p.I296L, p.L164P or p.T293N mutations, and no patients with these mutations successfully transferred. However, most individuals with mutations for which tolbutamide block was >73% did transfer successfully. The few patients with these mutations who could not transfer had a longer duration of diabetes than those who transferred successfully (18.2 vs 3.4 years, p = 0.032). There was no difference in pre-transfer HbA1c (p = 0.87), weight-for-age z scores (SD score; p = 0.12) or sex (p = 0.17).Conclusions/interpretationTransfer from insulin is successful for most KCNJ11 patients and is best predicted by the in vitro response of the specific mutation and the duration of diabetes. Knowledge of the specific mutation and of diabetes duration can help predict whether successful transfer to sulfonylureas is likely. This result supports the early genetic testing and early treatment of patients with neonatal diabetes aged under 6 months.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3921-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Histologic and Molecular Profile of Pediatric Insulinomas: Evidence of a Paternal Parent-of-Origin Effect

Acquired insulinomas are rare causes of hyperinsulinemic hypoglycemia in children and are much less common than focal lesions of congenital hyperinsulinism. The latter are known to be associated with isodisomy for paternally transmitted ATP-sensitive potassium channel mutations on 11p15; however, the molecular basis for pediatric insulinomas is not well characterized. The purpose of this study was to characterize the histopathological and molecular defects in a large group of 12 pediatric insulinomas seen at The Children's Hospital of Philadelphia. Twelve children with insulinomas were seen between 1971 and 2013, compared to 201 cases with focal congenital hyperinsulinism seen between 1997 and 2014. The age of insulinoma patients ranged from 4-16 years at the time of surgery. Features of MEN1 syndrome were present in five of the 12, including four cases with heterozygous mutations of MEN1 on 11q. Immunohistochemical analysis revealed nuclear loss of p57 staining consistent with loss of the maternal 11p15 allele in 11 of the 12 insulinomas, including all five MEN1-associated tumors. Imbalance of the paternal 11p allele was confirmed by single nucleotide polymorphism genotyping and methylation assays of the 11p imprinting control loci in four of five MEN1-associated tumors and six of seven sporadic insulinomas. In addition, single nucleotide polymorphism genotyping revealed extensive tumor aneuploidy beyond chromosome 11. These data indicate that MEN1 mutations are more common in insulinomas in children than in adults. Aneuploidy of chromosome 11 and other chromosomes is common in both MEN1 and non-MEN1 insulinomas. The novel observation of a paternal parent-of-origin effect in all MEN1 and most non-MEN1 tumors suggests a critical role for imprinted growth-regulatory genes in the 11p region in the genesis of β-cell endocrine tumors in children.

Infantile onset diabetes mellitus in developing countries - India.

Infantile onset diabetes mellitus (IODM) is an uncommon metabolic disorder in children. Infants with onset of diabetes mellitus (DM) at age less than one year are likely to have transient or permanent neonatal DM or rarely type 1 diabetes. Diabetes with onset below 6 mo is a heterogeneous disease caused by single gene mutations. Literature on IODM is scanty in India. Nearly 83% of IODM cases present with diabetic keto acidosis at the onset. Missed diagnosis was common in infants with diabetes (67%). Potassium channel mutation with sulphonylurea responsiveness is the common type in the non-syndromic IODM and Wolcott Rallison syndrome is the common type in syndromic diabetes. Developmental delay and seizures were the associated co-morbid states. Genetic diagnosis has made a phenomenal change in the management of IODM. Switching from subcutaneous insulin to oral hypoglycemic drugs is a major clinical breakthrough in the management of certain types of monogenic diabetes. Mortality in neonatal diabetes is 32.5% during follow-up from Indian studies. This article is a review of neonatal diabetes and available literature on IODM from India.

Abstract 16522: Structural Insights Into Destabilizing HERG PAS Domain Mutations Linked to Long Qt Syndrome

Introduction: Hundreds of HERG potassium channel mutations are linked to type 2 Long QT Syndrome (LQT2). Most mutations are trafficking defective but correctable by culturing cells at reduced temperature (27 C) or with the pore blocker E4031. For a few intracellular Per-ARNT-Sim (PAS) domain mutations, trafficking phenotypes have been shown to correlate with PAS domain stability. Since HERG intracellular domains are mutational hotspots containing 1/3 (&gt;100) of all LQT2 mutations, domain destabilization may be a major mechanism underlying LQT2. However, most mutations have not been studied and structural insights are lacking. Results: Using a recombinant PAS domain solubility assay as a proxy for stability, we tested 57 mutations and found a strong correlation between domain solubility and trafficking phenotype (trafficking defective and uncorrectable &lt; temperature correctable &lt; temperature and E4031 correctable &lt; trafficking competent). For buried residues V41 and C64, we used the protein stability prediction tool FoldX and immunoblot to show that domain stability and trafficking phenotype becomes more severe as the side chain becomes larger suggesting overpacking of the PAS domain core as a mechanism for LQT2-V41F and LQT2-C64W. This was further validated by designing second-site suppressor mutations to relieve potential side chain clashes. Immunoblot analysis showed that trafficking of LQT2-V41F is improved at 27 C with C39G or C64G, while C64A improved trafficking at 37 C. Immunoblot and current density analysis showed that trafficking of LQT2-C64W (3.8±0.8 pA/pF, n=4) is improved at 37 C with C39G (37.8±3.5 pA/pF, n=3) or Q61G (69.6±12.7 pA/pF, n=3) and LQT2-I42N (2.2±0.7 pA/pF, n=3) is improved at 37 C with Q61G (41.9±6.3 pA/pF, n=6). Additionally, site-saturation mutagenesis of residue V113 revealed loss of backbone (and not side chain) interactions as the structural basis for LQT2-delV113. Conclusions: This study identifies HERG PAS domain destabilization as a major mechanism underlying LQT2 and demonstrates a novel bioinformatics and structure-based method for analyzing disease-associated HERG mutations. These results are also a proof of concept that strategies to improve HERG domain stability could be a viable therapeutic approach.

A Disease Mutation Causing Episodic Ataxia Type I in the S1 Links Directly to the Voltage Sensor and the Selectivity Filter in Kv Channels.

Episodic ataxia (EA) is an inherited disease that leads to occasional loss of motor control in combination with variable other symptoms such as vertigo or migraine. EA type I (EA1), studied here, is caused by mutations in a voltage-gated potassium channel that contributes to the generation of electrical signals in the brain. The mechanism by which mutations in voltage-gated potassium channels lead to EA is still unknown and there is no consistent pharmacological treatment. By studying in detail one disease-causing mutation in Kv1.1, we describe a novel molecular mechanism distinct from mechanisms described previously. This mechanism contributes to the understanding of potassium channel function in general and might lead to a better understanding of how EA develops.

The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study

SummaryBackgroundTraditional genetic testing focusses on analysis of one or a few genes according to clinical features; this approach is changing as improved sequencing methods enable simultaneous analysis of several genes. Neonatal diabetes is the presenting feature of many discrete clinical phenotypes defined by different genetic causes. Genetic subtype defines treatment, with improved glycaemic control on sulfonylurea treatment for most patients with potassium channel mutations. We investigated the effect of early, comprehensive testing of all known genetic causes of neonatal diabetes.MethodsIn this large, international, cohort study, we studied patients with neonatal diabetes diagnosed with diabetes before 6 months of age who were referred from 79 countries. We identified mutations by comprehensive genetic testing including Sanger sequencing, 6q24 methylation analysis, and targeted next-generation sequencing of all known neonatal diabetes genes.FindingsBetween January, 2000, and August, 2013, genetic testing was done in 1020 patients (571 boys, 449 girls). Mutations in the potassium channel genes were the most common cause (n=390) of neonatal diabetes, but were identified less frequently in consanguineous families (12% in consanguineous families vs 46% in non-consanguineous families; p<0·0001). Median duration of diabetes at the time of genetic testing decreased from more than 4 years before 2005 to less than 3 months after 2012. Earlier referral for genetic testing affected the clinical phenotype. In patients with genetically diagnosed Wolcott-Rallison syndrome, 23 (88%) of 26 patients tested within 3 months from diagnosis had isolated diabetes, compared with three (17%) of 18 patients referred later (>4 years; p<0·0001), in whom skeletal and liver involvement was common. Similarly, for patients with genetically diagnosed transient neonatal diabetes, the diabetes had remitted in only ten (10%) of 101 patients tested early (<3 months) compared with 60 (100%) of the 60 later referrals (p<0·0001).InterpretationPatients are now referred for genetic testing closer to their presentation with neonatal diabetes. Comprehensive testing of all causes identified causal mutations in more than 80% of cases. The genetic result predicts the best diabetes treatment and development of related features. This model represents a new framework for clinical care with genetic diagnosis preceding development of clinical features and guiding clinical management.FundingWellcome Trust and Diabetes UK.

Calcium Mediated Mechanism of Early Afterdepolarizations in LQT2 Ventricular Myocytes

Background: Loss of function mutations in hERG potassium channels underlie the long QT syndrome type 2 (LQT2). LQT2 is associated with fatal ventricular arrhythmias promoted by triggered activity in the form of early afterdepolarizations (EADs). However, the cellular mechanism of EAD formation remains unexplored.Methods: We have investigated the mechanism of EAD formation in LQT2 ventricular myocytes using a physiologically detailed computational model of calcium (Ca2+) cycling and membrane voltage dynamics. This model bridges the submicron scale of individual couplons of plasmalemmal L-type Ca2+ channels clusters and sarcoplasmic reticulum (SR) Ca2+ release units (CRUs) and the whole cell. We incorporate the novel experimental finding that ryanodine receptors (RyRs) Ca2+ release channels are remodeled in ventricular mycoytes isolated from LQT2 transgenic rabbits; RyRs are hyperphosphorylated leading to enhanced channel activity and hence increased Ca2+ leak.Results: Computer simulations with RyR hyperactivity modeled as an increased rate of channel opening show that hyperactivity is causally linked to EAD formation. Under stimulation with the β-adrenergic agonist isoproterenol (ISO), LQT2 myocytes with hyperactive RyRs exhibit EADs together with decreased SR load and Ca2+ transient (CaT) amplitude, while myocytes with normal RyR activity exhibit a prolonged action potential without reductions of SR load and CaT amplitude. Simulations show that RyR hyperactivity shortens RyR refractoriness at the CRU level, resulting in late aberrant Ca2+ releases during repolarization. Those releases promote onset of EADs by driving the forward mode Na+-Ca2+ exchanger NCX1 current, which slows repolarization and allows reactivation of L-type Ca2+ current. Modeling predictions are in good agreement with experimental observations, which show that EADs in ISO-stimulated LQT2 myocytes are accompanied by late Ca2+ releases together with decreased SR load and CaT amplitude, and that both late releases and EADs are abolished by inhibition of CaMKII.

Impaired IKs channel activation by Ca2 +-dependent PKC shows correlation with emotion/arousal-triggered events in LQT1

BackgroundThe most common inherited cardiac arrhythmia, LQT1, is due to IKs potassium channel mutations and is linked to high risk of adrenergic-triggered cardiac events. We recently showed that although exercise-triggered events are very well treated by ß-blockers for these patients, acute arousal-triggered event rate were not significantly reduced after beta-blocker treatment, suggesting that the mechanisms underlying arousal-triggered arrhythmias may be different from those during exercise. IKs is strongly regulated by β-adrenergic receptor (β-AR) signaling, but little is known about the role of α1-AR-mediated regulation. Methods and resultsHere we show, using a combination of cellular electrophysiology and computational modeling, that IKs phosphorylation and α1-AR regulation via activation of calcium-dependent PKC isoforms (cPKC) may be a key mechanism to control channel voltage-dependent activation and consequently action potential duration (APD) in response to adrenergic-stimulus. We show that simulated mutation-specific combined adrenergic effects (β+α) on APD were strongly correlated to acute stress-triggered cardiac event rate for patients while β-AR effects alone were not. ConclusionWe were able to show that calcium-dependent PKC signaling is key to normal QT shortening during acute arousal and when impaired, correlates with increased rate of sudden arousal-triggered cardiac events. Our study suggests that the acute α1-AR-cPKC regulation of IKs is important for QT shortening in “fight-or-flight” response and is linked to decreased risk of sudden emotion/arousal-triggered cardiac events in LQT1 patients.

Human Slack Potassium Channel Mutations Increase Positive Cooperativity between Individual Channels

Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 (Slack) Na(+)-activated K(+) channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions.

GW25-e3159 Screening of potassium channel mutations in patients with atrial fibrillation

To identify gene mutations of potassium channels that contributed to the pathogenesis of atrial fibrillation. Genomic DNA was extracted from the peripheral blood of 124 patients with atrial fibrillation. The coding regions of genes including KCNE1 (minK), KCNE1L (KCNE5), KCNE2 (MiRP1), KCNE4 (MiRP3

Synergistic Restoring Effects of Isoproterenol and Magnesium on KCNQ1-Inhibited Bradycardia Cell Models Cultured in Microelectrode Array

Objectives: Bradycardia is caused by loss-of-function mutations in potassium channels that regulate phase 3 repolarization of the cardiac action potential. The purpose of this study is to monitor the effects of potassium channel (KCNQ1) inhibition and to evaluate the effects of isoproterenol (ISO) and MgSO₄ in restoring sinus rhythm in atrial cells. Methods: Microelectrode array was used to analyze conduction velocity, voltage amplitude and cycle length of atrial cells (HL-1). A combination of ISO and MgSO₄ was used to restore sinus rhythm in these cells. Results: mRNA expression levels of KCNQ1 (42.2 vs. 100%, p < 0.0001), connexin 43 (29.6 vs. 100%, p = 0.0033), atrial natriuretic peptide (31.0 vs. 100%, p = 0.0030), cardiac actin (38.2 vs. 100%, p < 0.0001) and α-myosin heavy chain (31.2 vs. 100%, p = 0.00254) were significantly lower in the KCNQ1 gene-inhibited group compared to the control group. When treated with MgSO₄ (1 m<smlcap>M</smlcap>) and ISO (10 μ<smlcap>M</smlcap>), conduction velocity (0.0208 ± 0.0036 vs. 0.0086 ± 0.0014 m/s, p = 0.0004) and voltage amplitude (1,210.78 ± 65.81 vs. 124.1 ± 13.30 μV, p < 0.0001) were higher, and cycle length (431.55 ± 2.05 vs. 1,015.15 ± 4.31 ms, p < 0.0001) was shorter than in the gene-inhibited group. Conclusion: Inhibition of sinus rhythm in the bradycardia cell model was recovered by treatment with ISO and MgSO₄, demonstrating the potency of combination therapy in the treatment of bradycardia.

Hyperphosphorylation of RyRs Underlies Triggered Activity in Transgenic Rabbit Model of LQT2 Syndrome

Loss-of function mutations in HERG potassium channels are associated with ventricular tachycardia and sudden cardiac death caused by stress. We aimed to investigate changes in Ca homeostasis in cardiomyocytes derived from LQT2 hearts and to determine whether these changes contribute to arrhythmogenic early afterdepolarizations (EADs) characteristic of LQT2 myocytes under β-adrenergic stimulation. Parameters of Ca handling were measured in ventricular myocytes isolated from normal and LQT2 hearts using confocal Ca imaging and whole-cell patch clamp. Ca imaging revealed no LQT2-mediated changes in amplitude of Ca transients and SR Ca content under basal conditions. Experiments in saponin-permeabilized cells using SR-entrapped low-affinity Ca indicator revealed enhanced RyR-mediated SR Ca leak and SERCA-mediated Ca uptake in LQT2 myocytes. Correspondingly, western blot analyses using phospho-specific antibodies showed that phosphorylation of both RyR and phospholamban is significantly higher in LQT2 CMs vs. controls at both PKA and CaMKII sites. In the presence of isoproterenol (50 nM) LQT2 CMs exhibited diminished Ca transient amplitudes and SR Ca content compared to controls. Stimulation of LQT2 CMs with isoproterenol resulted in prolongation of plateau of action potentials accompanied by aberrant Ca releases and phase 3 EADs, in contrast to controls. Importantly, preincubation of LQT2 CMs with CaMKII inhibitor KN93 (10 min, 500 nM) prevented ISO-mediated changes in AP duration, disturbances in Ca handling and EADs. Analysis of CaMKII activity revealed no differences between LQT2 and control heart tissues, while Western-blot analysis demonstrated ∼30% decrease in the abundance of catalytic subunit of protein phosphatase type 1 (PP1). These data suggest that hyperactive RyRs due to adaptive reduction in PP1 activity and thereby RyR hyperphosphorylation is a key contributor to enhanced triggered activity in hereditary LQT2 syndrome.

Abstract 18560: Defective Ca 2 + Homeostasis Contributes to Arrhythmia in Transgenic Rabbit Model of LQT2 Syndrome

Introduction: Loss-of function mutations in HERG potassium channels in Long QT2 syndrome are associated with sudden cardiac death triggered by sympathetic surge. In various models of cardiac disease changes in calcium (Ca) homeostasis, associated with upregulated plasmalemmal Na/Ca exchanger (NCX) and/or hyperactive ryanodine receptors (RyRs), have been linked to increased risk of arrhythmia. Methods and Results: The aims of this study were to investigate possible changes in Ca homeostasis in cardiomyocytes derived from from the hearts of LQT2 rabbits and to determine whether similar changes contribute to the triggering of early afterdepolarizations (EADs) characteristic of LQT2 myocytes under β-adrenergic stimulation. Parameters of Ca handling were measured in ventricular myocytes enzymatically isolated from LQT2 and littermate control hearts using confocal Ca imaging and whole cell patch clamp. Ca imaging revealed no changes in amplitude of Ca transients in intact myocytes and sarcoplasmic reticulum (SR) Ca content assessed by measuring amplitude of transients evoked by rapid application of caffeine. A two-fold increase in rate of decay of caffeine-induced Ca transients in LQT2 myocytes vs. controls indicated increased NCX activity. Experiments in saponin-permeabilized cells using a SR-entrapped low-affinity Ca indicator revealed ~2-fold increase in RyR-mediated SR Ca leak in LQT2 myocytes in comparison with controls. In contrast to controls, current-clamped LQT2 myocytes exposed to β-adrenergic agonist isoproterenol exhibited prolonged plateau of action potentials (AP) at -10 - 0 mV accompanied by aberrant Ca releases and phase 3 EADs. Importantly, complete exhaustion of SR [Ca] by incubation of LQT2 cells with SERCA inhibitor thapsigargin or 10 mM caffeine, shortened APD and completely abolished EADs. Conclusion: Functional changes in RyR and NCX underlie preserved systolic Ca transients in LQT2 myocytes under basal conditions and may contribute to stress-induced arrhythmia by maintaining the plateau of AP at voltages ideal for reactivation of plasmalemmal Ca channels and generation of EADs.

Congenital short QT syndrome: Landmarks of the newest arrhythmogenic cardiac channelopathy

Congenital or familial short QT syndrome is a genetically heterogeneous cardiac channelopathy without structural heart disease that has a dominant autosomal or sporadic pattern of transmission affecting the electric system of the heart. Patients present clinically with a spectrum of signs and symptoms including irregular palpitations due to episodes of paroxysmal atrialfibrillation, dizziness and fainting (syncope) and/or sudden cardiac death due to polymorphic ventricular tachycardia and ventricular fibrillation. Electrocardiographic (ECG) findings include extremely short QTc intervals (QTc interval ≤330 ms) not significantly modified with heart rate changes and T waves of great voltage witha narrow base. Electrophysiologic studies are characterized by significant shortening of atrial and ventricular refractory periods and arrhythmias induced by programmed stimulation. A few families have been identified with specific genotypes: 3 with mutations in potassium channels called SQT1 (Iks), SQT2 (Ikr) and SQT3 (Ik1). These 3 potassium channel variants are the "genetic mirror image" of long QT syndrome type 2, type 1 and Andersen-Tawil syndrome respectively because they exert opposite gain-of-function effects on the potassium channels in contrast to the loss-of-function of the potassium channels in the long QT syndromes. Three new variants with overlapping phenotypes affecting the slow inward calcium channels havealso been described. Finally, another variant with mixed phenotype affecting the sodium channel was reported. This review focuses the landmarks of this newest arrhythmogenic cardiac channelopathy on the main clinical, genetic, and proposed ECG mechanisms. In addition therapeutic options and the molecular autopsy of this fascinating primary electrical heart disease are discussed.

Abnormal electroencephalograms in patients with long QT syndrome

The long QT syndrome (LQTS) is an inherited cardiac channelopathy associated with syncope and sudden cardiac death due to ventricular arrhythmias. It is most frequently caused by potassium channel mutations. Potassium channels are also expressed in brain tissue and play an important role in idiopathic epilepsies. Recent reports have indicated that related potassium channel mutations may coexpress as concomitant epilepsy and LQTS. The purpose of this study was to explore cerebral activity by means of EEG recordings in individuals with LQTS related to potassium channel mutations. Seventeen individuals with confirmed LQTS related to potassium channel mutations (11 LQT1 and 6 LQT2) were prospectively studied with 21-channel electroencephalography (EEG) LQTS -related symptoms, comorbidity, medication, and QTc (12-lead ECG) were recorded. Sixteen healthy individuals previously studied with EEG served as a control group. All EEGs were reviewed by two independent neurophysiologists. EEG recordings were abnormal in 12 of 17 patients (71%) in the LQTS group, whereas abnormalities were present in only 2 of 16 healthy controls (13%; P <.01). In the LQTS group, all abnormal EEGs showed a combination of theta activity and sharp waves. Two patients showed additional delta activity. None of the patients had definite epileptic activity (spikes, spike waves). Abnormal electrical cerebral activity was identified more frequently in subjects with LQTS secondary to a potassium channel mutation compared with healthy controls. This result indicates a possible link between cardiac and cerebral channelopathy.

TASK-1 potassium channel mutations in atrial fibrillation

TASK-1 potassium channel mutations in atrial fibrillation

Primary aldosteronism and potassium channel mutations

To summarize and discuss data from recent studies implicating mutations in potassium channel genes in the pathogenesis of primary aldosteronism. Potassium channel gene variants are associated with the primary aldosteronism phenotype in animals (Kcnma1, TASK-1, and TASK-3) and humans (HERG and KCNJ5). Germline KCNJ5 mutations cause bilateral, familial primary aldosteronism with variable severity and genotype:phenotype correlations. Somatic KCNJ5 mutations occur in approximately 40% of aldosterone-producing adenomas, and are associated with younger age, female sex, more severe primary aldosteronism, lack of responsiveness of plasma aldosterone to upright posture, and zona fasciculata histology. Of five so far described, G151R and L168R are by far the most common. KCNJ5 mutations lead to reduced K⁺/Na⁺ channel selectivity and Na⁺ influx, predisposing to cell membrane depolarization, increased calcium influx, increased expression of genes promoting aldosterone synthesis, and increased aldosterone production by adrenocortical cells. How they lead to adrenal cell proliferation and tumor development is less well understood. These findings shed considerable light on the pathophysiology of primary aldosteronism with the potential to lead to new diagnostic approaches and treatments.

Genetics of adrenocortical disease

Disease states characterized by abnormal cellular function or proliferation frequently reflect aberrant genetic information. By revealing disease-specific DNA mutations, we gain insight into normal physiology, pathophysiology, potential therapeutic targets and are better equipped to evaluate an individual's disease risks. This review examines recent advances in our understanding of the genetic basis of adrenal cortical disease. Important advances made in the past year have included identification of KCNJ5 potassium channel mutations in the pathogenesis of both aldosterone-producing adenomas and familial hyperaldosteronism type III; characterization of phosphodiesterase 11A as a modifier of phenotype in Carney complex caused by protein kinase, cAMP-dependent, regulatory subunit, type-I mutations; the finding of 11β-hydroxysteroid dehydrogenase type I mutations as a novel mechanism for cortisone reductase deficiency; and demonstration of potential mortality benefit in pursuing comprehensive presymptomatic screening for patients with Li-Fraumeni syndrome, including possible reduction in risks associated with adrenocortical carcinoma. This research review provides a framework for the endocrinologist to maintain an up-to-date understanding of adrenal cortical disease genetics.