ankyrin-B Syndrome Research Articles

Association of ANK2 Mutation and Massive Myocardial Calcification: A Case Report

<h3>Introduction</h3> A 35-year-old man with no prior history of cardiovascular diseases was admitted with progressive exertional chest discomfort. Physical examination revealed irregular heart rhythm and an ejection murmur at the aortic area. EKG showed atrial fibrillation, and chest X-ray, calcification within the cardiac silhouette. Laboratory tests were all within normal ranges, including serological and inflammatory tests. <h3>Case Report</h3> An echocardiogram demonstrated diffuse myocardium calcification and intense mitral- aortic fibrocalcification, causing severe stenosis and moderate regurgitation, with a dilated left ventricle (LV) and moderate systolic dysfunction, akinesia of the inferolateral walls and hypokinesia of the anterior walls. A 128-row multidetector CT showed massive calcification affecting the aortic and mitral valves, the right ventricle, the left atrium wall and all the segments of the LV, preserving only the basal septum. Cardiovascular magnetic resonance imaging 1.5T revealed diffuse myocardial thickening, matching the areas seen on CT (figure). These areas were hypointense on the SSFP cine images and on T1- and T2-weighted images and had no late gadolinium enhancement (LGE). However, there was LGE in the underlying myocardium, in a non-ischemic distribution. Pericardium and coronary arteries were preserved. Genetic analysis identified a rare heterozygous variant of uncertain significance, c.10702C>T(p.Arg3568Trp), in ANK2 gene. <h3>Summary</h3> Ankyrin-B, also known as Ankyrin-2, is encoded by the ANK2 gene, which plays critical roles in the localization and stabilization of ion transporters and ion channels in cardiomyocytes. The Ankyrin-B syndrome has been associated to long QT syndrome and torsades depointes, but there are no reports of myocardial calcification. The patient was found to be a candidate for cardiac transplantation and is currently on the waiting list.

Mechanisms and Alterations of Cardiac Ion Channels Leading to Disease: Role of Ankyrin-B in Cardiac Function.

Ankyrin-B (encoded by ANK2), originally identified as a key cytoskeletal-associated protein in the brain, is highly expressed in the heart and plays critical roles in cardiac physiology and cell biology. In the heart, ankyrin-B plays key roles in the targeting and localization of key ion channels and transporters, structural proteins, and signaling molecules. The role of ankyrin-B in normal cardiac function is illustrated in animal models lacking ankyrin-B expression, which display significant electrical and structural phenotypes and life-threatening arrhythmias. Further, ankyrin-B dysfunction has been associated with cardiac phenotypes in humans (now referred to as “ankyrin-B syndrome”) including sinus node dysfunction, heart rate variability, atrial fibrillation, conduction block, arrhythmogenic cardiomyopathy, structural remodeling, and sudden cardiac death. Here, we review the diverse roles of ankyrin-B in the vertebrate heart with a significant focus on ankyrin-B-linked cell- and molecular-pathways and disease.

Long QT Syndrome and Sinus Bradycardia-A Mini Review.

Congenital long-QT syndrome (LQTS) is an inherited cardiac disorder characterized by the prolongation of ventricular repolarization, susceptibility to Torsades de Pointes (TdP), and a risk for sudden death. Various types of congenital LQTS exist, all due to specific defects in ion channel-related genes. Interestingly, almost all of the ion channels affected by the various types of LQTS gene mutations are also expressed in the human sinoatrial node (SAN). It is therefore not surprising that LQTS is frequently associated with a change in basal heart rate (HR). However, current data on how the LQTS-associated ion channel defects result in impaired human SAN pacemaker activity are limited. In this mini-review, we provide an overview of known LQTS mutations with effects on HR and the underlying changes in expression and kinetics of ion channels. Sinus bradycardia has been reported in relation to a large number of LQTS mutations. However, the occurrence of both QT prolongation and sinus bradycardia on a family basis is almost completely limited to LQTS types 3 and 4 (LQT3 and Ankyrin-B syndrome, respectively). Furthermore, a clear causative role of this sinus bradycardia in cardiac events seems reserved to mutations underlying LQT3.

Ankyrins and Spectrins in Cardiovascular Biology and Disease.

Ankyrins are adaptor proteins critical for the expression and targeting of cardiac membrane proteins, signaling molecules, and cytoskeletal elements. Findings in humans and animal models have highlighted the in vivo roles for ankyrins in normal physiology and in cardiovascular disease, most notably in cardiac arrhythmia. For example, human ANK2 loss-of-function variants are associated with a complex array of electrical and structural phenotypes now termed “ankyrin-B syndrome,” whereas alterations in the ankyrin-G pathway for Nav channel targeting are associated with human Brugada syndrome. Further, both ankyrin-G and -B are now linked with acquired forms of cardiovascular disease including myocardial infarction and atrial fibrillation. Spectrins are ankyrin-associated proteins and recent studies support the critical role of ankyrin-spectrin interactions in normal cardiac physiology as well as regulation of key ion channel and signaling complexes. This review will highlight the roles of ankyrins and spectrins in cardiovascular physiology as well as illustrate the link between the dysfunction in ankyrin- and spectrin-based pathways and disease.

The evolving role of ankyrin-B in cardiovascular disease

Over the past decade, ankyrin-B has been identified as a prominent player in cardiac physiology. Ankyrin-B has a multitude of functions, with roles in expression, localization, and regulation of proteins critical for cardiac excitability, cytoskeletal integrity, and signaling. Furthermore, human ANK2 variants that result in ankyrin-B loss of function are associated with "ankyrin-B syndrome," a complex cardiac phenotype that may include bradycardia and heart rate variability, conduction block, atrial fibrillation, QT interval prolongation, and potentially fatal catecholaminergic polymorphic ventricular tachycardia. However, our understanding of the molecular mechanisms underlying ankyrin-B function at baseline and in disease is still not fully developed owing to the complexity of ankyrin-B gene regulation, number of ankyrin-B-associated molecules, multiple roles of ankyrin-B in the heart and other organs that modulate cardiac function, and a host of unexpected clinical phenotypes. In this review, we summarize known roles of ankyrin-B in the heart and the impact of ankyrin-B dysfunction in animal models and in human disease as well as highlight important new findings illustrating the complexity of ankyrin-B signaling.

Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome.

Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of Northern British Columbia largely because of a known mutation in KCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation. Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel ANK2 c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant. We identify the first disease-causing ANK2 variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of ANK2 in targeting and stabilization of key structural and signaling molecules in cardiac cells.

Ankyrin-B Syndrome: A Case of Sinus Node Dysfunction, Atrial Fibrillation and Prolonged QT in a Young Adult

Ankyrin-B protein is involved in regulating expression and localisation of cardiac ion channels and transporters. Mutations of the ANK2 gene in the rare condition Ankyrin-B syndrome result in loss of function of the ankyrin-B protein which in turn leads to abnormal regulation of intracellular sodium and calcium and a predisposition to cardiac arrhythmia including torsades de pointes. We describe a rare case of this condition characterised by sinus node dysfunction, atrial fibrillation and prolonged QT syndrome in a young patient with a family history of sudden death. The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications, insertion of a permanent pacemaker for sinus node dysfunction, or a cardioverter defibrillator for those at high-risk of sudden death from torsades de pointes.

Genetics of Long QT Syndrome

Long QT syndrome (LQTS) is a potentially life-threatening cardiac arrhythmia characterized by delayed myocardial repolarization that produces QT prolongation and increased risk for torsades des pointes (TdP)-triggered syncope, seizures, and sudden cardiac death (SCD) in an otherwise healthy young individual with a structurally normal heart. Currently, there are three major LQTS genes (KCNQ1, KCNH2, and SCN5A) that account for approximately 75% of the disorder. For the major LQTS genotypes, genotype-phenotype correlations have yielded gene-specific arrhythmogenic triggers, electrocardiogram (ECG) patterns, response to therapies, and intragenic and increasingly mutation-specific risk stratification. The 10 minor LQTS-susceptibility genes collectively account for less than 5% of LQTS cases. In addition, three atypical LQTS or multisystem syndromic disorders that have been associated with QT prolongation have been described, including ankyrin-B syndrome, Anderson-Tawil syndrome (ATS), and Timothy syndrome (TS). Genetic testing for LQTS is recommended in patients with either a strong clinical index of suspicion or persistent QT prolongation despite their asymptomatic state. However, genetic test results must be interpreted carefully.

Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis

Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca(2+) channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, whereas defects in Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue. These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue levels that favor the common manifestation of atrial arrhythmias and SAN dysfunction.

Atrial Fibrillation and Sinus Node Dysfunction in Human Ankyrin-B Syndrome: A Computational Analysis

Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca2+ channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, while defects in Na+/Ca2+ exchanger and Na+/K+ ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue.These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue level that favor the common manifestation of atrial arrhythmias and SAN dysfunction.

Fra global til lokal - ny forståelse av den elektromekaniske koblingen i hjertet

The coupling between depolarisation and the heart's contraction is fundamental to the physiology and pathophysiology of the heart. This paper describes how the coupling depends on the interaction between proteins in "microdomains" in the heart muscle cells. The paper is based on the authors'' own research and on a discretionary selection of articles found by means of a literature search in PubMed. Essential aspects of the physiology and pathophysiology of the heart must be understood through the interaction between proteins in delimited parts of the cells. The significance of the binding protein ankyrin-B and the Ca2+ channel IP3R (inositol 1,4,5-triphosphate receptor) is best understood in this context. Abnormal function of ankyrin-B and IP3R is involved in congenital diseases with increased risk of arrhythmia and in weakened contractility and arrhythmia in connection with heart failure. The pathophysiological mechanism involves a change in Ca2+ homeostasis locally in the heart muscle cells. Normal cardiac electromechanical coupling depends on control of ionic homeostasis in intracellular microdomains. Insight into the interaction between proteins in these "local neighbourhoods" provides new explanations for the pathophysiology of heart disease and paves the way for further research on arrhythmia mechanisms in hereditary diseases such as ankyrin-B syndrome.

Defining new insight into atypical arrhythmia: a computational model of ankyrin-B syndrome

Normal cardiac excitability depends on the coordinated activity of specific ion channels and transporters within specialized domains at the plasma membrane and sarcoplasmic reticulum. Ion channel dysfunction due to congenital or acquired defects has been linked to human cardiac arrhythmia. More recently, defects in ion channel-associated proteins have been associated with arrhythmia. Ankyrin-B is a multifunctional adapter protein responsible for targeting select ion channels, transporters, cytoskeletal proteins, and signaling molecules in excitable cells, including neurons, pancreatic β-cells, and cardiomyocytes. Ankyrin-B dysfunction has been linked to cardiac arrhythmia in human patients and ankyrin-B heterozygous (ankyrin-B(+/-)) mice with a phenotype characterized by sinus node dysfunction, susceptibility to ventricular arrhythmias, and sudden death ("ankyrin-B syndrome"). At the cellular level, ankyrin-B(+/-) cells have defects in the expression and membrane localization of the Na(+)/Ca(2+) exchanger and Na(+)-K(+)-ATPase, Ca(2+) overload, and frequent afterdepolarizations, which likely serve as triggers for lethal cardiac arrhythmias. Despite knowledge gathered from mouse models and human patients, the molecular mechanism responsible for cardiac arrhythmias in the setting of ankyrin-B dysfunction remains unclear. Here, we use mathematical modeling to provide new insights into the cellular pathways responsible for Ca(2+) overload and afterdepolarizations in ankyrin-B(+/-) cells. We show that the Na(+)/Ca(2+) exchanger and Na(+)-K(+)-ATPase play related, yet distinct, roles in intracellular Ca(2+) accumulation, sarcoplasmic reticulum Ca(2+) overload, and afterdepolarization generation in ankyrin-B(+/-) cells. These findings provide important insights into the molecular mechanisms underlying a human disease and are relevant for acquired human arrhythmia, where ankyrin-B dysfunction has recently been identified.

Ankyrin-B Syndrome: Enhanced Cardiac Function Balanced by Risk of Cardiac Death and Premature Senescence

Here we report the unexpected finding that specific human ANK2 variants represent a new example of balanced human variants. The prevalence of certain ANK2 (encodes ankyrin-B) variants range from 2 percent of European individuals to 8 percent in individuals from West Africa. Ankyrin-B variants associated with severe human arrhythmia phenotypes (eg E1425G, V1516D, R1788W) were rare in the general population. Variants associated with less severe clinical and in vitro phenotypes were unexpectedly common. Studies with the ankyrin-B+/− mouse reveal both benefits of enhanced cardiac contractility, as well as costs in earlier senescence and reduced lifespan. Together these findings suggest a constellation of traits that we term “ankyrin-B syndrome”, which may contribute to both aging-related disorders and enhanced cardiac function.

A Failure to Adapt

The development of serious, potentially lethal cardiac arrhythmias is determined by a complex integration of factors, including, but not limited to, common and rare genetic variants that determine the responses to gene-gene and gene-environment interactions. Even the rare “simple” channelopathies that cause long-QT syndrome (LQTS) and a host of other potentially lethal arrhythmias exhibit a complex set of phenotypes of varying severity and overlapping features. Ankyrins are a family of adapter proteins, first identified in the erythrocyte membrane, that mediate the localization of a diverse group of cellular proteins. Three genes in the mammalian genome encode ankyrins that share a similar global architecture but exhibit distinct expression patterns and functions: ANK1 encodes ankyrin-R, which exhibits a more restricted expression; ANK2 (chromosome 4q25–27) encodes the more broadly distributed ankyrin-B; and ANK3 encodes the ankyrin-G for general or global. Ankyrins bind a number of ion motive proteins essential to normal cardiac electrophysiology, including the Na+-Ca2+ exchanger; inositol 1,4,5-triphosphate receptor; Na+-K+ ATPase; and the voltage-dependent sodium channel (NaV1.5) By the very nature of the role of ankyrins in excitation and contraction in cardiac myocytes, it is understandable that variants in ankyrin-B originally described in a family with congenital LQTS1 would exhibit protean electrical phenotypes. Indeed, in the original LQTS cohort, sinus node dysfunction and atrial fibrillation have been described,1,2 and other electrophysiological abnormalities such as conduction block, idiopathic ventricular fibrillation, and catecholaminergic ventricular tachycardia have been included under the rubric of ankyrin-B syndrome.3 A mutation in the ankyrin binding domain of NaV1.5 has been associated with defective ankyrin-G binding and Brugada syndrome.4 Article p …

Defining the Cellular Phenotype of “Ankyrin-B Syndrome” Variants

Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. We performed a comprehensive screen of ANK2 in populations (control, congenital arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a spectrum of cellular phenotypes. We then characterized the relative severity of loss-of-function properties of all 9 nonsynonymous ANK2 variants identified to date in primary cardiomyocytes and identified a range of in vitro phenotypes, including wild-type, simple loss-of-function, and severe loss-of-function activity, seen with the variants causing severe human phenotypes. We present the first description of differences in cellular phenotypes conferred by specific ANK2 variants. We propose that the various degrees of ankyrin-B loss of function contribute to the range of severity of cardiac dysfunction. These data identify ANK2 variants as modulators of human arrhythmias, provide the first insight into the clinical spectrum of "ankyrin-B syndrome," and reinforce the role of ankyrin-B-dependent protein interactions in regulating cardiac electrogenesis.

Ankyrins and Human Disease: What the Electrophysiologist Should Know

The coordinate activity of ion channels and transporters in cardiac muscle is critical for normal excitation-contraction coupling and cardiac rhythm. In the past decade, human gene variants, which alter ion channel biophysical properties, have been linked with fatal cardiac arrhythmias. Ankyrins are a family of "adaptor" proteins, which play critical roles in the proper expression and membrane localization of ion channels and transporters in excitable and nonexcitable cells. Recent findings demonstrate a new paradigm for human cardiac arrhythmia based not on gene mutations that affect channel biophysical properties, but instead on mutations that affect ion channel/transporter localization at excitable membranes in heart. Human ANK2 mutations are associated with "ankyrin-B syndrome" (an atypical arrhythmia syndrome with risk of sudden cardiac death). Human gene mutations, which affect ankyrin-G-based pathways for voltage-gated Na(v) channel localization, are associated with Brugada syndrome, a second potentially fatal arrhythmia. Together, these data demonstrate the importance of the molecular events involved in the cellular organization of membrane domains in excitable cells. Moreover, these data define an exciting new field of cardiac "channelopathies" due to defects in proper channel targeting/localization.

Cardiac ankyrins: Essential components for development and maintenance of excitable membrane domains in heart

Ankyrins are intracellular proteins required for the biogenesis and maintenance of membrane domains in both excitable and non-excitable cells. Ankyrin family polypeptides have been implicated in the targeting and stabilization of membrane proteins including ion channels, transporters, exchangers and cell adhesion molecules in diverse tissues and cell types including the erythrocyte, kidney, lung and brain. Dysfunction in ankyrin-based pathways has previously been linked to abnormalities in vertebrate physiology including spherocytosis and anemia, ataxia and axonal degeneration. Recent findings have illuminated the importance of ankyrin-based pathways in excitable cells of the heart. Specifically, two ankyrin gene products, 220-kDa ankyrin-B and 190-kDa ankyrin-G, have been implicated in the targeting of structurally diverse membrane ion channels and transporters to excitable membrane domains in cardiomyocytes. Moreover, findings in humans and mice have determined the critical nature of ankyrin-based pathways for normal cardiac excitability. Reduction of ankyrin-B expression levels in mice or the presence of ankyrin-B loss-of-function mutations in humans leads to 'ankyrin-B syndrome', a cardiac disease with a spectrum of clinical presentations including bradycardia, ventricular tachycardia and sudden cardiac death in response to catecholaminergic stimuli. Ankyrin-G is required for expression of the major cardiac voltage-gated Na(v) channel, Na(v)1.5, at specialized cardiac membrane domains. Human variants in SCN5A (encodes Na(v)1.5) that block Na(v)1.5 interaction with ankyrin-G lead to loss of Na(v)1.5 membrane expression and Brugada syndrome. Together, these recent findings in heart reinforce the importance of ankyrin-based pathways for normal vertebrate physiology and raise exciting new questions regarding the cellular roles for ankyrin polypeptides in cardiac and other excitable cells. While ankyrins have only been recently identified in heart, our current understanding suggests that elucidating the roles of ankyrins in organizing and targeting protein complexes to excitable membrane domains will yield important insights into the molecular basis of cardiac arrhythmias.