From Genome to Physiome: Integrative Models of Cardiac Excitation

The last decade has generated extensive information on the genetic and molecular basis of disease. A major challenge remains the integration of this information into the physiological environment of the functioning cell and tissue. This article illustrates the use of computational biology in meeting this challenge in the context of cardiac excitation and arrhythmia. (1) Genetics to Cell Function: Mutations that alter the kinetics of the cardiac sodium channel, I _Na, give rise to a congenital form of the long QT syndrome that can lead to sudden death. Using a computer model of the cardiac cell, we simulated the effects of the mutations on the action potential, demonstrating its prolongation at slow rate and the development of arrhythmogenic early afterdepolarizations due to reactivation of L-type Ca channels, I _Ca(L) [Clancy and Rudy, Nature (London) 400:566, 1999]. (2) Multicellular Tissue: Slow conduction is an important property of propagation arrhythmias (reentry). Very slow conduction is supported by reduced intercellular coupling through gap junctions. Using a multicellular fiber model, we have shown that slow conduction is very stable and, in contrast to normal conduction which depends solely on I _Na requires a major contribution from I _Ca(L) (Shaw and Rudy, Circ. Res. 81:727, 1997). © 2000 Biomedical Engineering Society. PAC00: 8719Hh, 8719Nn, 8717Nn, 8710+e     

The genetic basis of Brugada syndrome: A mutation update

Brugada syndrome (BrS) is a condition characterized by a distinct ST‐segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss‐of‐function mutations in SCN5A, which encodes the α‐subunit of the Na_v1.5 sodium ion channel conducting the depolarizing I_Na current, causes 15–20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol‐3‐phosphate dehydrogenase‐1 like protein; CACNA1C, which encodes the α‐subunit of the Ca_v1.2 ion channel conducting the depolarizing I_L,Ca current; CACNB2, which encodes the stimulating β2‐subunit of the Ca_v1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes β‐subunits of the Na_v1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory β‐subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I_to current. BrS exhibits variable expressivity, reduced penetrance, and “mixed phenotypes,” where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described. Hum Mutat 30:1–11, 2009. © 2009 Wiley‐Liss, Inc.     

Sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis

Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage‐gated, sodium (Na⁺) channel α‐subunits (Na_v1.5). We summarize experimental studies of physiological and clinical consequences of loss‐of‐function Na⁺ channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a^+/? hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Na_v1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Na_v1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Na_v1.5 haploinsufficient males in producing clinical arrhythmia.     

A homozygous SCN5A mutation in a severe,recessive type of cardiac conduction disease

Cardiac sodium channels are key players in the generation and propagation of action potentials in the human heart. Heterozygous mutations in the SCN5A gene have been found to be associated with long QT syndrome, Brugada syndrome, and sinus node dysfunction (SND). Recently, overlapping arrhythmia phenotypes have been reported as well. Here we describe a novel recessive SCN5A mutation in a family originating from the German minority in White Russia. Four affected children with a history of early cardiac arrhythmia encompassing SND, conduction disease, and severe ventricular arrhythmias, are homozygous carriers of a novel SCN5A missense mutation (p.I230T) in the channel protein. Interestingly, the heterozygous mutation carriers had neither significant ECG abnormalities nor a history of cardiac events. Heterologous expression of SCN5A(I230T) channels revealed normal protein transport but altered biophysical sodium channel properties. Voltage range of both activation and inactivation were shifted in a way that resulted in decreased sodium current and loss of channel function. In conclusion, we describe a rare clinical condition with a novel SCN5A mutation causing a new type of complex cardiac arrhythmia. Unlike most previously reported sodium channelopathies, this overlap syndrome displays recessive inheritance characteristics and does not seem to follow simple Mendelian rules.© 2010 Wiley‐Liss, Inc.     

SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes

SKF-96365 (1-(beta-[3-(4-methoxy-phenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride) is a general TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in cardiovascular system. Recent reports showed that SKF-96365 induced a reduction in cardiac conduction. The present study investigates whether the reduced cardiac conduction caused by SKF-96365 is related to the blockade of voltage-gated sodium current (I _Na) in rat ventricular myocytes using the whole-cell patch voltage-clamp technique. It was found that SKF-96365 inhibited I _Na in rat ventricular myocytes in a concentration-dependent manner. The compound (1 μM) negatively shifted the potential of I _Na availability by 9.5 mV, increased the closed-state inactivation of I _Na, and slowed the recovery of I _Na from inactivation. The inhibition of cardiac I _Na by SKF-96365 was use-dependent and frequency-dependent, and the IC₅₀ was decreased from 1.36 μM at 0.5 Hz to 1.03, 0.81, 0.61, 0.56 μM at 1, 2, 5, 10 Hz, respectively. However, the selective TRPC3 antagonist Pyr3 decreased cardiac I _Na by 8.5 % at 10 μM with a weak use and frequency dependence. These results demonstrate that the TRPC channel antagonist SKF-96365 strongly blocks cardiac I _Na in use-dependent and frequency-dependent manners. Caution should be taken for interpreting the alteration of cardiac electrical activity when SKF-96365 is used in native cells as a TRPC antagonist.     

Channelopathies: ion channel defects linked to heritable clinical disorders

Electrical signals are critical for the function of neurones, muscle cells, and cardiac myocytes. Proteins that regulate electrical signalling in these cells, including voltage gated ion channels, are logical sites where abnormality might lead to disease. Genetic and biophysical approaches are being used to show that several disorders result from mutations in voltage gated ion channels. Understanding gained from early studies on the pathogenesis of a group of muscle diseases that are similar in their episodic nature (periodic paralysis) showed that these disorders result from mutations in a gene encoding a voltage gated Na⁺ channel. Their characterisation as channelopathies has served as a paradigm for other episodic disorders. For example, migraine headache and some forms of epilepsy have been shown to result from mutations in voltage gated Ca²⁺ channel genes, while long QT syndrome is known to result from mutations in either K⁺ or Na⁺ channel genes. This article reviews progress made in the complementary fields of molecular genetics and cellular electrophysiology which has led to a better understanding of voltage gated ion channelopathies in humans and mice.


Keywords: ion channel genetics; ion channel physiopathology; channelopathies; hereditary diseases     

A Missense Mutation in the Sodium Channel β2 Subunit Reveals SCN2B as a New Candidate Gene for Brugada Syndrome

Brugada Syndrome (BrS) is a familial disease associated with sudden cardiac death. A 20%–25% of BrS patients carry genetic defects that cause loss‐of‐function of the voltage‐gated cardiac sodium channel. Thus, 70%–75% of patients remain without a genetic diagnosis. In this work, we identified a novel missense mutation (p.Asp211Gly) in the sodium β2 subunit encoded by SCN2B, in a woman diagnosed with BrS. We studied the sodium current (I_Na) from cells coexpressing Na_v1.5 and wild‐type (β2WT) or mutant (β2D211G) β2 subunits. Our electrophysiological analysis showed a 39.4% reduction in I_Na density when Na_v1.5 was coexpressed with the β2D211G. Single channel analysis showed that the mutation did not affect the Na_v1.5 unitary channel conductance. Instead, protein membrane detection experiments suggested that β2D211G decreases Na_v1.5 cell surface expression. The effect of the mutant β2 subunit on the I_Na strongly suggests that SCN2B is a new candidate gene associated with BrS.     

Computer simulation of wild-type and mutant human cardiac Na+ current

Long QT syndrome (LQTS) and Brugada syndrome (BrS) are inherited diseases predisposing to ventricular arrhythmias and sudden death. Genetic studies linked LQTS and BrS to mutations in genes encoding for cardiac ion channels. Recently, two novel missense mutations at the same codon in the gene encoding the cardiac Na⁺ channel (SCN5A) have been identified: Y1795C (causing the LQTS phenotype) and Y1795H (causing the BrS phenotype). Functional studies in HEK293 cells showed that both mutations alter the inactivation of Na⁺ current and cause a sustained Na⁺ current upon depolarisation. In this paper, a nine state Markov model was used to simulate the Na⁺ current in wild-type Na⁺ cardiac channel and the current alterations observed in Y1795C and Y1795H mutant channels. The model includes three distinct closed states, a conducting open state and five inactivation states (one fast-, two intermediate- and two closed-inactivation). Transition rates between these states were identified on the basis of previously published voltage-clamp experiments. The model was able to reproduce the experimental Na⁺ current in mutant channels just by altering the assignment of model parameters with respect to wild-type case. Parameter assignment was validated by performing action potential clamp experiments and comparing experimental and simulated I _Na current. The Markov model was subsequently introduced in the Luo–Rudy model of ventricular myocyte to investigate “in silico” the consequences on the ventricular cell action potential of the two mutations. Coherently with their phenotypes, the Y1795C mutation prolongs the action potential, while the Y1795H mutation causes only negligible changes in action potential morphology.     

Review: Metabolic cardiomyopathy and conduction system defects in children

Metabolic cardiomyopathies include amino acid, lipid and mitochondrial disorders, as well as storage diseases. A number of metabolic disorders are associated with both myopathy and cardiomyopathy. These include the glycogen storage diseases, ie, acid maltase deficiency (infantile, childhood, and adult onset), McArdle disease, and debrancher and brancher deficiencies. Disorders of lipid metabolism include systemic carnitine deficiency and abnormalities of carnitine palmitoyltransferase (CPT), long-chain acyl-CoA dehydrogenase, and multiple acyl-CoA dehydrogenase. Disorders of mitochondrial metabolism affect complex I, II, III, IV and V, in addition to multiple respiratory chain defects. These may cause either hypertrophic or dilated cardiomyopathy. In addition, cardiomyopathy is frequently a component part of the storage disorders, including mucopolysaccharidosis, mucolipidosis, Fabry disease, gangliosidosis, and neuronal ceroid lipofuscinosis. Primary hypertrophic cardiomyopathy is caused by mutations in one of the genes that encode proteins of the cardiac sarcomere. Mutations in different genes are attended by different prognoses and different risks of sudden death. Mutations of the genes for myosin binding protein C (MBPC) and tropomyosin have low penetrance and cause mild forms of primary hypertrophic cardiomyopathy, while mutations of the troponin T and B-myosin genes carry a worse prognosis. Conduction disorders result in cardiac arrhythmias that may be fatal. Histiocytoid cardiomyopathy is usually an autosomal recessive disorder that results in the presence of abnormal Purkinje cells that interfere with normal cardiac conduction. Other conduction defects include arrhythmogenic right ventricular dysplasia (ARVD), congenital heart block, noncompaction of the left ventricle, and long Q-T syndrome (LQTS). The genetic loci for LQTS reside usually in the potassium channel, and, less frequently, in the sodium channel (channelopathies). Although the histological appearance of some of these disorders may be diagnostic, molecular analysis is necessary to define clearly the particular type of cardiomyopathy.     

Sodium channelopathies of skeletal muscle result from gain or loss of function

Five hereditary sodium channelopathies of skeletal muscle have been identified. Prominent symptoms are either myotonia or weakness caused by an increase or decrease of muscle fiber excitability. The voltage-gated sodium channel Na_V1.4, initiator of the muscle action potential, is mutated in all five disorders. Pathogenetically, both loss and gain of function mutations have been described, the latter being the more frequent mechanism and involving not just the ion-conducting pore, but aberrant pores as well. The type of channel malfunction is decisive for therapy which consists either of exerting a direct effect on the sodium channel, i.e., by blocking the pore, or of restoring skeletal muscle membrane potential to reduce the fraction of inactivated channels.     

Human KATP channelopathies: diseases of metabolic homeostasis

Assembly of an inward rectifier K⁺ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATP-sensitive K⁺ (K_ATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. K_ATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, K_ATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in K_ATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in K_ATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, K_ATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). K_ATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-at-large and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within K_ATP channel genes and the spectrum of genotype–phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human K_ATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy.     

Pathophysiology of HCN channels

Hyperpolarization-activated cation currents termed I _f/h are observed in many neurons and cardiac cells. Four genes (HCN1-4) encode the channels underlying these currents. New insights into the pathophysiological significance of HCN channels have been gained recently from analyses of mice engineered to be deficient in HCN genes. Lack of individual subunits results in markedly different phenotypes. Disruption of HCN1 impairs motor learning but enhances spatial learning and memory. Deletion of HCN2 results in absence epilepsy, ataxia, and sinus node dysfunction. Mice lacking HCN4 die during embryonic development and develop no sinoatrial node-like action potentials. In the present review, we summarize the physiology and pathophysiology of HCN channel family members based primarily on information from the transgenic mouse models and on data from human patients carrying defects in HCN4 channels.     

The impact of emotion valence on brain processing of behavioral inhibitory control: spatiotemporal dynamics

Voltage-gated sodium channels (VGSCs) play important roles in maintaining the excitability of hippocampal neurons. The present study investigated the effects of resibufogenin (RBG, a main component of bufadienolides) on voltage-gated sodium channel currents (I_Na) in rat hippocampal neurons using whole-cell patch clamp recording. According to the results, RBG activated I_Na in a concentration-dependent manner. RBG at 1 μM concentration could alter some channel kinetics of I_Na, such as activation thresholds, steady-state activation and inactivation curves, time constant of recovery, and activity-dependent attenuation of I_Na. RBG influenced peak amplitude, overshoot and half-width of the evoked single action potential, and simultaneously lessened the firing rate of evoked repetitive firing. These findings suggested that I_Na is probably a target of RBG, which may explain the mechanisms for the pathological effects of RBG on central nervous system.     

Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels

Voltage-gated Ca²⁺ channels couple membrane depolarization to Ca²⁺-dependent intracellular signaling events. This is achieved by mediating Ca²⁺ ion influx or by direct conformational coupling to intracellular Ca²⁺ release channels. The family of Ca_v1 channels, also termed L-type Ca²⁺ channels (LTCCs), is uniquely sensitive to organic Ca²⁺ channel blockers and expressed in many electrically excitable tissues. In this review, we summarize the role of LTCCs for human diseases caused by genetic Ca²⁺ channel defects (channelopathies). LTCC dysfunction can result from structural aberrations within their pore-forming α1 subunits causing hypokalemic periodic paralysis and malignant hyperthermia sensitivity (Ca_v1.1 α1), incomplete congenital stationary night blindness (CSNB2; Ca_v1.4 α1), and Timothy syndrome (Ca_v1.2 α1; reviewed separately in this issue). Ca_v1.3 α1 mutations have not been reported yet in humans, but channel loss of function would likely affect sinoatrial node function and hearing. Studies in mice revealed that LTCCs indirectly also contribute to neurological symptoms in Ca²⁺ channelopathies affecting non-LTCCs, such as Ca_v2.1 α1 in tottering mice. Ca²⁺ channelopathies provide exciting disease-related molecular detail that led to important novel insight not only into disease pathophysiology but also to mechanisms of channel function.     

Phosphorylation of cardiac voltage‐gated sodium channel: Potential players with multiple dimensions

Cardiomyocytes are highly coordinated cells with multiple proteins organized in micro domains. Minor changes or interference in subcellular proteins can cause major disturbances in physiology. The cardiac sodium channel (Na_V1.5) is an important determinant of correct electrical activity in cardiomyocytes which are localized at intercalated discs, T‐tubules and lateral membranes in the form of a macromolecular complex with multiple interacting protein partners. The channel is tightly regulated by post‐translational modifications for smooth conduction and propagation of action potentials. Among regulatory mechanisms, phosphorylation is an enzymatic and reversible process which modulates Na_V1.5 channel function by attaching phosphate groups to serine, threonine or tyrosine residues. Phosphorylation of Na_V1.5 is implicated in both normal physiological and pathological processes and is carried out by multiple kinases. In this review, we discuss and summarize recent literature about the (a) structure of Na_V1.5 channel, (b) formation and subcellular localization of Na_V1.5 channel macromolecular complex, (c) post‐translational phosphorylation and regulation of Na_V1.5 channel, and (d) how these phosphorylation events of Na_V1.5 channel alter the biophysical properties and affect the channel during disease status. We expect, by reviewing these aspects will greatly improve our understanding of Na_V1.5 channel biology, physiology and pathology, which will also provide an insight into the mechanism of arrythmogenesis at molecular level.     

Effects of Mixed Herbal Extracts from Parched Puerariae Radix, Gingered Magnoliae Cortex, Glycyrrhizae Radix and Euphorbiae Radix (KIOM-79) on Cardiac Ion Channels and Action Potentials

KIOM-79, a mixture of ethanol extracts from four herbs (parched Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae radix and Euphorbiae radix), has been developed for the potential therapeutic application to diabetic symptoms. Because screening of unexpected cardiac arrhythmia is compulsory for the new drug development, we investigated the effects of KIOM-79 on the action potential (AP) and various ion channel currents in cardiac myocytes. KIOM-79 decreased the upstroke velocity (V_max) and plateau potential while slightly increased the duration of action potential (APD). Consistent with the decreased V_max and plateau potential, the peak amplitude of Na⁺ current (I_Na) and Ca²⁺ current (I_Ca,L) were decreased by KIOM-79. KIOM-79 showed dual effects on hERG K⁺ current; increase of depolarization phase current (I_depol) and decreased tail current at repolarization phase (I_tail). The increase of APD was suspected due to the decreased I_tail. In computer simulation, the change of cardiac action potential could be well simulated based on the effects of KIOM-79 on various membrane currents. As a whole, the influence of KIOM-79 on cardiac ion channels are minor at concentrations effective for the diabetic models (0.1-10 µg/mL). The results suggest safety in terms of the risk of cardiac arrhythmia. Also, our study demonstrates the usefulness of the cardiac computer simulation in screening drug-induced long-QT syndrome.     

Sodium current block caused by group IIb cations in calf Purkinje fibres and in guinea-pig ventricular myocytes

The action of group IIb cations [Cadmium (Cd²⁺), Zinc (Zn²⁺), Mercury (Hg²⁺)] on the cardiac fast sodium current (I _Na) was investigated in calf Purkinje fibres and in ventricular cells isolated from guinea-pig hearts. In calf Purkinje fibres, I _Na was depressed by submillimolar concentrations of Zn²⁺ and Hg²⁺. With both cations, the current reduction occurred at all voltages in the range of current activation and the voltage dependence of peak current was unchanged. The degree of peak current inhibition depended on the cation concentration but not on voltage. The position of the inactivation curve on the voltage axis was unaltered at cation concentrations giving substantial current inhibition, and moved to the right only with concentration exceeding 1–1.5 mM. These effects can be interpreted as due to I _Na channel blockade. The action of Zn²⁺ and Hg²⁺ was similar to that described earlier of Cd²⁺ on Purkinje fibres (DiFrancesco et al. 1985b). I _Na was also inhibited by group IIb cations in isolated guinea-pig ventricular cells. Depression of I _Na by Cd²⁺, Zn²⁺ and Hg²⁺ was essentially voltage-independent, in agreement with its being caused by channel block. The dependence of I _Na block by Cd²⁺ upon external Na concentration [Na⁺ ₀] was investigated in ventricular myocytes. The fraction of I _Na block by 0.1 mM CdCl₂ was 0.50 at 140 mM, 0.81 at 70 mM and 0.83 at 35 mM [Na⁺]₀. A similar increase of block efficiency at low [Na⁺ ₀] was observed with 0.05 mM CdCl₂. In both the Purkinje fibre and the ventricular cell, the order of potency of I _Na block by group IIb cations was Hg²⁺> Zn²⁺> Cd²⁺. Manganese (Mn²⁺, 2–5 mM), an ion of group VIIa, also depressed the I _Na in Purkinje fibres and ventricular myocytes. This effect was however due mainly to a positive shift on the voltage dependence of current kinetics rather than to a reduction of the conductance of the channel (G _Na), and can be accounted for by an ion-screening action of Mn²⁺ on the external membrane surface. The block by group IIb cations is a typical property of cardiac Na⁺ channels and characterizes the cardiac as opposed to other types of Na⁺ channel. Offprint request to: D. DiFrancesco     

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies

SCN5A mutations involving the α-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the α-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non-dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome.     

Kir 2.1 channelopathies: the Andersen–Tawil syndrome

As a multisystem disorder, Andersen–Tawil syndrome (ATS) is rather unique in the family of channelopathies. The full spectrum of the disease is characterized by ventricular arrhythmias, dysmorphic features, and periodic paralysis. Most ATS patients have a mutation in the ion channel gene, KCNJ2, which encodes the inward rectifier K⁺ channel Kir2.1, a component of the inward rectifier I _K1. I _K1 provides repolarizing current during the most terminal phase of repolarization and is the primary conductance controlling the diastolic membrane potential. Thus, ATS is a disorder of cardiac repolarization. The chapter will discuss the most recent data concerning the genetic, cellular, and clinical data underlying this unique disorder.