Researchers identify causative gene in mouse model of inherited lethal arrhythmia

A research group led by University of Tsukuba has discovered a mouse pedigree that presents spontaneous sudden cardiac death attributed to inherited ventricular arrhythmia. This was identified through electrocardiographic screening of a large-scale, randomly mutagenized mouse library.

A novel missense mutation in the ryanodine receptor 2 (RyR2) was identified as the cause of sudden cardiac death in these mice. These findings, published in the journal Proceedings of the National Academy of Sciences, are expected to enhance the understanding of the pathogenesis of ventricular arrhythmias and sudden cardiac death, and facilitate the development of novel therapies.

Inherited arrhythmias, a serious disorder caused by genetic abnormalities in ion channels and related molecules that regulate cardiomyocyte electrical activity can lead to fatal arrhythmias and sudden cardiac death.

Although significant progress has been made in identifying causative molecules and mechanisms, allowing the development of various therapies, including antiarrhythmic drugs, radiofrequency catheter ablation, and implantable cardioverter-defibrillators, a fundamental treatment remains elusive.

Thus, there is a pressing need to develop more effective treatment and prevention methods, as well as disease models that can aid in advancing such strategies.

To investigate the pathogenesis of inherited arrhythmias, which are a major cause of sudden cardiac death among young individuals, researchers conducted electrocardiographic screening within a large-scale mouse library with random genetic mutations.

They successfully established a mouse pedigree exhibiting inherited arrhythmias that spontaneously lead to lethal arrhythmias. Further genetic analysis identified the causative gene as a novel missense mutation in ryanodine receptor 2 (RyR2: p.I4093V), crucial for regulating intracellular calcium essential for cardiomyocyte contraction.

This mouse model, which exhibits severe symptoms of age-related cardiac function decline and sudden cardiac death within the first year of life, is anticipated to contribute greatly to the elucidation of inherited arrhythmia’s pathogenesis and the assessment of drug efficacy.