Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient-Derived Cardiac Myocytes

Stem Cell Reports
Chad R FrasierLori L Isom

Abstract

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Most DS patients carry de novo variants in SCN1A, resulting in Nav1.1 haploinsufficiency. Because SCN1A is expressed in heart and in brain, we proposed that cardiac arrhythmia contributes to SUDEP in DS. We generated DS patient and control induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). We observed increased sodium current (INa) and spontaneous contraction rates in DS patient iPSC-CMs versus controls. For the subject with the largest increase in INa, cardiac abnormalities were revealed upon clinical evaluation. Generation of a CRISPR gene-edited heterozygous SCN1A deletion in control iPSCs increased INa density in iPSC-CMs similar to that seen in patient cells. Thus, the high risk of SUDEP in DS may result from a predisposition to cardiac arrhythmias in addition to seizures, reflecting expression of SCN1A in heart and brain.

Citations

Jan 25, 2020·Epilepsy Currents·Jana E JonesUNKNOWN NINDS/AES Benchmarks Stewards Committee
Mar 25, 2020·Annals of Clinical and Translational Neurology·Sharon ShmuelyRoland D Thijs
Aug 15, 2020·Human Molecular Genetics·George Andrew S InglisAndrew Escayg
Sep 20, 2020·Brain and Behavior·Maxine DibuéMarcel A Kamp
Sep 19, 2019·Epilepsy Currents·Rui Li, Gordon F Buchanan
Nov 27, 2019·World Journal of Stem Cells·Maria Teresa ValentiDonato Zipeto
Sep 21, 2019·Neuropharmacology·Zane R LybrandJenny Hsieh
Dec 24, 2019·Experimental Neurology·Alexandra N PetrucciGordon F Buchanan
Feb 4, 2021·Nature Reviews. Neuroscience·Miriam H MeislerWenxi Yu
Feb 25, 2021·The Application of Clinical Genetics·Christine KeywanIngrid A Holm
Oct 30, 2021·Frontiers in Genome Editing·Amy McTagueManju A Kurian

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Methods Mentioned

BETA
transgenic
biopsies
biopsy
PCR

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