The Role of Voltage-Gated Sodium Channel Gene Scn1b in the Developing Pediatric Heart
Edokobi, Nnamdi
2021
Abstract
Sudden Unexpected Death in Epilepsy (SUDEP) is the most devastating consequence of epilepsy, yet little is understood about its causes and no biomarkers exist to identify at-risk patients. Although the underlying mechanism(s) of SUDEP are unclear, evidence suggests that in addition to the seizures, breathing abnormalities, autonomic dysfunction, and cardiac arrhythmias may all play a role. Variants in SCN1B, encoding voltage-gated sodium channel (Nav) β1/β1B subunits, are linked to neurological and cardiovascular diseases that predispose patients to sudden premature death, including developmental and epileptic encephalopathy type 52 (DEE52, OMIM 617350), Brugada Syndrome 5 (OMIM 612838), and Atrial Fibrillation Familial 13 (OMIM 615377). Several studies published by our laboratory and others have demonstrated, using heterologous and native cells, that β1/ 1B subunits are multi-functional proteins that play critical roles in cellular excitability, cell adhesion, and transcriptional regulation. The Scn1b-null mouse model exhibits neurological dysfunction, cardiac dysfunction, and premature death by the third week of life, highlighting the clinical relevancy of variants in this gene. The work presented in this thesis aimed to further our understanding about the role of SCN1B in cardiac pathophysiology. Although the mechanism of SUDEP is complicated, we hypothesize that SCN1B DEE52 variants predispose patients to underlying cardiac abnormalities, thereby, increasing their risk of SUDEP. This hypothesis is explored in the following chapters. The first chapter reviews Navs biochemistry and the role of and subunits in cardiac physiology. Chapter 2 focuses on the role of the Scn1b in the regulation of atrial physiology using the Scn1b null mouse model. We show differential expression of genes that are associated with atrial dysfunction in Scn1b null hearts. Remarkably, neonatal Scn1b null hearts showed a significant accumulation of atrial collagen, increased susceptibility to pacing-induced AF in vivo, sinoatrial node dysfunction, and increased numbers of cholinergic neurons in ganglia that innervate the sinoatrial node. Administration of atropine reduced the incidence of AF in null mice, implicating autonomic influence. Finally, we found prolonged action potential duration and increased late sodium current density, with no change in transient sodium current density, in acutely isolated null atrial myocytes compared to wildtype. These results demonstrate a critical role for Scn1b in early postnatal atrial development. Chapter 3 presents work aimed to understand the mechanism of the SCN1B-linked DEE missense variant c.265c>T, predicting p.R89C, in heterologous cells and patient derived induced pluripotent stem cell cardiomyocytes (iPSC- CMs). In this detailed investigation, we determined that the patient iPSC- CMs have aberrant excitability, with similar properties as acutely isolated ventricular myocytes from Scn1b-null mice, including increased sodium current and action potential prolongation. Based on these findings, we concluded that the SCN1B-p.R89C variant may predispose patients to cardiac dysfunction in addition to severe epilepsy. This novel work provides important new insights into understanding the pathophysiological roles of Nav-β1 subunits in human pediatric cardiac cells. Taken together, this work demonstrates that SCN1B loss of function significantly impacts the developing heart in addition to the developing brain.Deep Blue DOI
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Sudden Death in Epilepsy Neuronal and cardiac physiology Voltage gated sodium channels
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