ArticleProceedings of the National Academy of Sciences of the United States of America2016
Leaky RyR2 channels unleash a brainstem spreading depolarization mechanism of sudden cardiac death.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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45 citing papers in PubMed, 1 synthesis or guideline pooled it, 62 citations in OpenAlex.
- Systematic Review of the Genetics of Sudden Unexpected Death in Epilepsy: Potential Overlap With Sudden Cardiac Death and Arrhythmia-Related Genes.Journal of the American Heart Association · 2020Pooled it
- Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.The Journal of clinical investigation · 2018Trial
- Loss of cyclin-dependent kinase-like 5 results in susceptibility to audiogenic seizures in mice.Epilepsia open · 2026Article
- The bed nucleus of the stria terminalis as a neuromodulatory target for refractory epilepsy.Frontiers in network physiology · 2026Review
- CRISPR/Cas9-mediatedFrontiers in physiology · 2026Article
- Spreading depolarization in neurocritical care: a review of SD'S pathophysiological continuum and clinical translation.Frontiers in human neuroscience · 2026Review
- Persistent Na+ current couples spreading depolarization to seizures in Scn8a gain-of-function mice.Brain : a journal of neurology · 2025Article
- Genetics, manifestations, and management of catecholaminergic polymorphic ventricular tachycardia.Current opinion in cardiology · 2025Review
- Sudden Unexpected Death in Epilepsy: Central Respiratory Chemoreception.International journal of molecular sciences · 2025Review
- Organellular imagingbioRxiv : the preprint server for biology · 2024Article
- Challenges and future directions of SUDEP models.Lab animal · 2024Review
- Brain Gene Regulatory Networks Coordinate Nest Construction in Birds.Molecular biology and evolution · 2024Article
- Epigenomic tomography for probing spatially defined chromatin state in the brain.Cell reports methods · 2024Article
- Dynamic dysregulation of transcriptomic networks in brainstem autonomic nuclei during hypertension development in the female spontaneously hypertensive rat.Physiological genomics · 2024Article
- Molecular Pathways and Animal Models of Arrhythmias.Advances in experimental medicine and biology · 2024Article
- Cardiac arrhythmia and epilepsy genetic variants in sudden unexpected death in epilepsy.Frontiers in neurology · 2024Article
- Strain-dependent effects on neurobehavioral and seizure phenotypes inbioRxiv : the preprint server for biology · 2023Article
- TRPM7 kinase mediates hypomagnesemia-induced seizure-related death.Scientific reports · 2023Article
- Gene mutations in comorbidity of epilepsy and arrhythmia.Journal of neurology · 2023Review
- In vivo delivery of CRISPR-Cas9 genome editing components for therapeutic applications.Biomaterials · 2022Review
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3 authors at 1 institution in 1 country.
Funding
Abstract
Cardiorespiratory failure is the most common cause of sudden unexplained death in epilepsy (SUDEP). Genetic autopsies have detected "leaky" gain-of-function mutations in the ryanodine receptor-2 (RyR2) gene in both SUDEP and sudden cardiac death cases linked to catecholaminergic polymorphic ventricular tachycardia that feature lethal cardiac arrhythmias without structural abnormality. Here we find that a human leaky RyR2 mutation, R176Q (RQ), alters neurotransmitter release probability in mice and significantly lowers the threshold for spreading depolarization (SD) in dorsal medulla, leading to cardiorespiratory collapse. Rare episodes of sinus bradycardia, spontaneous seizure, and sudden death were detected in RQ/+ mutant mice in vivo; however, when provoked, cortical seizures frequently led to apneas, brainstem SD, cardiorespiratory failure, and death. In vitro studies revealed that the RQ mutation selectively strengthened excitatory, but not inhibitory, synapses and facilitated SD in both the neocortex as well as brainstem dorsal medulla autonomic microcircuits. These data link defects in neuronal intracellular calcium homeostasis to the vulnerability of central autonomic brainstem pathways to hypoxic stress and implicate brainstem SD as a previously unrecognized site and mechanism contributing to premature death in individuals with leaky RYR2 mutations.
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