Last update 19 Sep 2024
Andersen Syndrome
Last update 19 Sep 2024
Basic Info
Synonyms ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS, ANDERSEN SYNDROME, ANDERSEN-TAWIL SYNDROME + [34] |
Introduction A form of inherited long QT syndrome (or LQT7) that is characterized by a triad of potassium-sensitive periodic paralysis, VENTRICULAR ECTOPIC BEATS, and abnormal features such as short stature, low-set ears, and SCOLIOSIS. It results from mutations of KCNJ2 gene which encodes a channel protein (INWARD RECTIFIER POTASSIUM CHANNELS) that regulates resting membrane potential. |
Related
Optimal Drug Therapy for the Suppression of Ventricular Arrhythmias in Andersen-Tawil Syndrome and Multifocal Ectopic Purkinje-related Premature Contractions: a Series of N-of-1 Trials
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Therapeutic Trial of Potassium and Acetazolamide in Andersen-Tawil Syndrome
100 Clinical Results associated with Andersen Syndrome
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100 Translational Medicine associated with Andersen Syndrome
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18 Jan 2024Heart rhythm
The Kir2.1-NaV1.5 Channelosome and its role in Arrhythmias in Inheritable Cardiac Diseases.
Review
Author: Lilian K Gutiérrez ; Ana I Moreno-Manuel ; José Jalife
Sudden cardiac death in children and young adults is a relatively rare but tragic event whose pathophysiology is unknown at the molecular level. Evidence indicates that the main cardiac sodium channel (NaV1.5) and the strong inward rectifier potassium channel (Kir2.1) physically interact and form macromolecular complexes (channelosomes) with common partners, including adapter, scaffolding and regulatory proteins that help them traffic together to their eventual membrane microdomains. Most important, dysfunction of either or both ion channels has direct links to hereditary human diseases. For example, certain mutations in the KCNJ2 gene encoding the Kir2.1 protein result in Andersen-Tawil syndrome type 1 and alter both inward rectifier potassium (IK1) and sodium inward currents (INa). Similarly, trafficking-deficient mutations in the gene encoding the NaV1.5 protein (SCN5A) result in Brugada syndrome and may also disturb both INa and IK1. Moreover, gain-of-function mutations in KCNJ2 result in short QT syndrome type 3, which is extremely rare but highly arrhythmogenic, and can modify Kir2.1-NaV1.5 interactions in a mutation-specific way, further highlighting the relevance of channelosomes in ion channel diseases. By expressing mutant proteins that interrupt or modify Kir2.1 or NaV1.5 function in animal models and patient-specific iPSC-CMs, investigators are defining for the first time the mechanistic framework of how mutation-induced dysregulation of the Kir2.1-NaV1.5 channelosome affects cardiac excitability resulting in arrhythmias and sudden death in different cardiac diseases.
28 Jul 2023Muscle & nerve
Muscle MRI in periodic paralysis shows myopathy is common and correlates with intramuscular fat accumulation.
Article
Author: Vinojini Vivekanandam ; Karen Seutterlin ; Emma Matthews ; John Thornton ; Dipa Jayaseelan ; Sachit Shah ; Jasper M Morrow ; Tarek Yousry ; Michael G Hanna
INTRODUCTION/AIMS:
The periodic paralyses are muscle channelopathies: hypokalemic periodic paralysis (CACNA1S and SCN4A variants), hyperkalemic periodic paralysis (SCN4A variants), and Andersen-Tawil syndrome (KCNJ2). Both episodic weakness and disabling fixed weakness can occur. Little literature exists on magnetic resonance imaging (MRI) in muscle channelopathies. We undertake muscle MRI across all subsets of periodic paralysis and correlate with clinical features.
METHODS:
A total of 45 participants and eight healthy controls were enrolled and underwent T1-weighted and short-tau-inversion-recovery (STIR) MRI imaging of leg muscles. Muscles were scored using the modified Mercuri Scale.
RESULTS:
A total of 17 patients had CACNA1S variants, 16 SCN4A, and 12 KCNJ2. Thirty-one (69%) had weakness, and 9 (20%) required a gait-aid/wheelchair. A total of 78% of patients had intramuscular fat accumulation on MRI. Patients with SCN4A variants were most severely affected. In SCN4A, the anterior thigh and posterior calf were more affected, in contrast to the posterior thigh and posterior calf in KCNJ2. We identified a pattern of peri-tendinous STIR hyperintensity in nine patients. There were moderate correlations between Mercuri, STIR scores, and age. Intramuscular fat accumulation was seen in seven patients with no fixed weakness.
DISCUSSION:
We demonstrate a significant burden of disease in patients with periodic paralyses. MRI intramuscular fat accumulation may be helpful in detecting early muscle involvement, particularly in those without fixed weakness. Longitudinal studies are needed to assess the role of muscle MRI in quantifying disease progression over time and as a potential biomarker in clinical trials.
08 Jun 2023bioRxiv : the preprint server for biology
Extracellular cysteine disulfide bond break at Cys122 disrupts PIP 2 -dependent Kir2.1 channel function and leads to arrhythmias in Andersen-Tawil Syndrome.
Author: Francisco M Cruz ; Álvaro Macías ; Ana I Moreno-Manuel ; Lilian K Gutiérrez ; María Linarejos Vera-Pedrosa ; Isabel Martínez-Carrascoso ; Patricia Sánchez Pérez ; Juan Manuel Ruiz Robles ; Francisco J Bermúdez-Jiménez ; Aitor Díaz-Agustín ; Fernando Martínez de Benito ; Salvador Arias Santiago ; Aitana Braza-Boils ; Mercedes Martín-Martínez ; Marta Gutierrez-Rodríguez ; Juan A Bernal ; Esther Zorio ; Juan Jiménez-Jaimez ; José Jalife
Background:
Andersen-Tawil Syndrome Type 1 (ATS1) is a rare heritable disease caused by mutations in the strong inwardly rectifying K + channel Kir2.1. The extracellular Cys122-to-Cys154 disulfide bond in the Kir2.1 channel structure is crucial for proper folding, but has not been associated with correct channel function at the membrane. We tested whether a human mutation at the Cys122-to-Cys154 disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing the open state of the channel.
Methods and Results:
We identified a Kir2.1 loss-of-function mutation in Cys122 (c.366 A>T; p.Cys122Tyr) in a family with ATS1. To study the consequences of this mutation on Kir2.1 function we generated a cardiac specific mouse model expressing the Kir2.1 C122Y mutation. Kir2.1 C122Y animals recapitulated the abnormal ECG features of ATS1, like QT prolongation, conduction defects, and increased arrhythmia susceptibility. Kir2.1 C122Y mouse cardiomyocytes showed significantly reduced inward rectifier K + (I K1 ) and inward Na + (I Na ) current densities independently of normal trafficking ability and localization at the sarcolemma and the sarcoplasmic reticulum. Kir2.1 C122Y formed heterotetramers with wildtype (WT) subunits. However, molecular dynamic modeling predicted that the Cys122-to-Cys154 disulfide-bond break induced by the C122Y mutation provoked a conformational change over the 2000 ns simulation, characterized by larger loss of the hydrogen bonds between Kir2.1 and phosphatidylinositol-4,5-bisphosphate (PIP 2 ) than WT. Therefore, consistent with the inability of Kir2.1 C 122 Y channels to bind directly to PIP 2 in bioluminescence resonance energy transfer experiments, the PIP 2 binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch-clamping the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing PIP 2 concentrations.
Conclusion:
The extracellular Cys122-to-Cys154 disulfide bond in the tridimensional Kir2.1 channel structure is essential to channel function. We demonstrated that ATS1 mutations that break disulfide bonds in the extracellular domain disrupt PIP 2 -dependent regulation, leading to channel dysfunction and life-threatening arrhythmias.
CLINICAL PERSPECTIVE:
NOVELTY AND SIGNIFICANCE: What is known? Andersen-Tawil Syndrome Type 1 (ATS1) is a rare arrhythmogenic disease caused by loss-of-function mutations in KCNJ2 , the gene encoding the strong inward rectifier potassium channel Kir2.1 responsible for I K1 . Extracellular Cys 122 and Cys 154 form an intramolecular disulfide bond that is essential for proper Kir2.1 channel folding but not considered vital for channel function. Replacement of Cys 122 or Cys 154 residues in the Kir2.1 channel with either alanine or serine abolished ionic current in Xenopus laevis oocytes. What new information does this article contribute? We generated a mouse model that recapitulates the main cardiac electrical abnormalities of ATS1 patients carrying the C122Y mutation, including prolonged QT interval and life-threatening ventricular arrhythmias.We demonstrate for the first time that a single residue mutation causing a break in the extracellular Cys122-to-Cys154 disulfide-bond leads to Kir2.1 channel dysfunction and arrhythmias in part by reorganizing the overall Kir2.1 channel structure, disrupting PIP2-dependent Kir2.1 channel function and destabilizing the open state of the channel.Defects in Kir2.1 energetic stability alter the functional expression of the voltage-gated cardiac sodium channel Nav1.5, one of the main Kir2.1 interactors in the macromolecular channelosome complex, contributing to the arrhythmias.The data support the idea that susceptibility to arrhythmias and SCD in ATS1 are specific to the type and location of the mutation, so that clinical management should be different for each patient.Altogether, the results may lead to the identification of new molecular targets in the future design of drugs to treat a human disease that currently has no defined therapy.
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