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 are expected to enhance the understanding of the pathogenesis of ventricular arrhythmias and sudden cardiac death, and facilitate the development of novel therapies.

Tsukuba, Japan—Inherited arrhythmias, a serious disorders 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 leads 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.

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This work was supported by the World Premier International Research Center Initiative from Ministry of Education, Culture, Sports, Science and Technology; Japan Agency for Medical Research and Development (JP21zf0127005); Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (17H06095 and 22H04918, 16H05045 to K.A., 19H03404, 19K07105, and 23659410); Basis for Supporting Innovative Drug Discovery and Life Science Research (JP21am0101080); the Vehicle Racing Commemorative Foundation (6237); and Funding Program for World-Leading Innovative R&D on Science and Technology from JSPS.

Original Paper

Title of original paper:

An inherited life-threatening arrhythmia model established by screening randomly mutagenized mice

Journal:

Proceedings of the National Academy of Sciences of the United States of America (PNAS)

DOI:

10.1073/pnas.2218204121

Correspondence

Professor YANAGISAWA Masashi
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba

Associate Professor MURAKOSHI Nobuyuki
Institute of Medicine, University of Tsukuba

Dr. OKABE Yuta
Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Current position: Head doctor at Cardiovascular Medicine, Ibaraki Prefectural Central Hospital

Appointed Associate Professor KUREBAYASHI Nagomi
Associate Professor MURAYAMA Takashi
Department of Cellular and Molecular Pharmacology, Juntendo University Graduate School of Medicine

Assistant Professor INOUE Hana
Department of Physiology, Tokyo Medical University

Related Link

International Institute for Integrative Sleep Medicine (WPI-IIIS)

Institute of Medicine