Unravel the mystery of Andersen Tawil Syndrome type 1

Some scientists have managed to reveal the cause of arrhythmias and sudden death in the disease called Andersen-Tawil Syndrome type 1. This is a rare disease with autosomal dominant inheritance characterized by frequent ventricular arrhythmias, associated with developmental disorders of a highly variable degree. .

The scientists who have made the discovery are from two teams from the National Center for Cardiovascular Research (CNIC) in Spain.

Led by Drs. José Jalife and Juan Antonio Bernal, researchers have discovered a previously unknown fundamental function of Kir2.1 channels, which control essential electrical properties of excitable cells such as cardiac muscle, skeletal muscle, and neurons.

Thanks to a combination of confocal microscopy images, and biochemical and electrophysiological tests, these teams have revealed a double location and function of the Kir2.1 channels controlling potassium fluxes through the cellular and endoplasmic membranes, being involved in the control of electrical activity and excitation-contraction coupling, respectively.

In the study, the CNIC teams have shown that these two different Kir2.1 protein microdomains are present in different species and in different muscle cells, indicating that they support relevant conserved and generalized functions in cells.

In addition, as Dr. Bernal points out, the study has also carried out a detailed characterization of a new mouse model of the disease.

In the recent study, a new potential molecular mechanism is proposed to explain the arrhythmias, skeletal muscle weakness and periodic paralysis reported in patients with Andersen-Tawil Syndrome type 1. The pathology is caused by mutations in proteins that form channels of potassium regulators of electrical activity and of the intracellular calcium cycle in the heart and skeletal muscle. (Image: CNIC)

Intravenous injection of adeno-associated virus (AAV) containing a mutant KCNJ2 gene, encoding a Kir2.1 protein deficient in trafficking to its physiological location in heart cells, into live animals helped the study authors find a new explanation. at the molecular level of life-threatening arrhythmias that occur in patients with ATS1.

“These arrhythmias overlap with the arrhythmias of another equally malignant inherited disease called catecholaminergic polymorphic ventricular tachycardia (CPVT),” explains Dr. Jalife.

In a recent review of other research results by the same team and published in the academic journal Cardiovascular Research, ATS1 manifests as a triad of symptoms including ventricular arrhythmias, periodic paralysis, and dysmorphic features caused by loss mutations. of function in KCNJ2, the gene that encodes the Kir2.1 protein, but the mechanisms of the arrhythmias have been unknown until now.

“The mouse model -explains Dr. Álvaro Macías, first author of the new study- recapitulates the cardiac electrical abnormalities found in ATS1 patients, including the high burden of arrhythmia and the susceptibility to tachycardia/ventricular fibrillation (VT/VF) responsible of sudden death”.

The data presented now propose a new potential molecular mechanism to explain the arrhythmias, skeletal muscle weakness, and periodic paralysis reported in ATS1 patients.

“Importantly, they also show that treatment with flecainide, a drug commonly used in the clinical setting and which sometimes fails to control arrhythmias in patients with ATS1, substantially exacerbates the ATS1 phenotype and increases the likelihood of arrhythmias in the ATS1 model. mouse,” adds Dr. Jalife.

These latest data, continues Jalife, “warn clinicians about the use of this drug that, depending on the specific case, could be harmful to patients with this disease.”

In summary, the dual role of Kir2.1 should lead to novel and more effective therapies for ATS1 and other overlapping disorders related to abnormal calcium dynamics, whether inherited like CPVT, but possibly also acquired like heart failure affecting to millions of people around the world.

The new study is titled “Kir2.1 dysfunction at the sarcolemma and the sarcoplasmic reticulum causes arrhythmias in a mouse model of Andersen–Tawil syndrome type 1.” And it has been published in the academic journal Nature Cardiovascular Research. (Source: CNIC)