Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/29726
Title: Rare SUDEP SCN5A variants cause changes in channel function implicating cardiac arrhythmia as a cause of death.
Austin Authors: Soh, Ming S;Bagnall, Richard D;Semsarian, Christopher;Scheffer, Ingrid E ;Berkovic, Samuel F ;Reid, Christopher A
Affiliation: The Florey Institute of Neuroscience and Mental Health
Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, NSW, Australia..
Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, VIC, Australia..
Faculty of Medicine and Health, The University of Sydney, NSW, Australia..
Department of Paediatrics, University of Melbourne, Royal Children's Hospital, VIC, Australia..
Epilepsy Research Centre
Issue Date: 9-Apr-2022
Date: 2022
Publication information: Epilepsia 2022; online first: 9 April
Abstract: Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of premature death in epilepsy. The underlying pathological mechanisms are likely to be multi-factorial. Cardiac arrhythmia has been suggested as a cause of death in some patients with SUDEP. SCN5A encodes the cardiac Nav 1.5 sodium channel. SCN5A variants that result in either loss or gain of channel function cause cardiac arrhythmias. Rare SCN5A variants have been reported in SUDEP cases but the impact of these variants on channel function is unknown. Here we use whole-cell voltage clamp recordings to perform functional analyses of rare SCN5A SUDEP variants, p.V223G, p.I397V and p.R523C. Expression and biophysical properties including activation, inactivation and recovery from inactivation were probed. Each SCN5A variant significantly impacted human NaV 1.5 channel function indicating that they could cause cardiac arrhythmias. The patient carrying the p.R523C variant was on lamotrigine, an antiseizure medication implicated in SUDEP. Therapeutic concentration of lamotrigine caused a slowing of the rate of recovery from inactivation and a hyperpolarizing shift in the voltage of inactivation of human NaV 1.5 wild-type, but not p.R523C channels, implicating a gene-by-drug interaction. These data suggest that SCN5A arrhythmogenic variants may confer increased risk of sudden death in individuals with epilepsy.
URI: https://ahro.austin.org.au/austinjspui/handle/1/29726
DOI: 10.1111/epi.17254
ORCID: https://orcid.org/0000-0002-5689-2082
https://orcid.org/0000-0002-2311-2174
https://orcid.org/0000-0003-4580-841X
https://orcid.org/0000-0002-1457-8028
Journal: Epilepsia
PubMed URL: 35397174
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/35397174/
Type: Journal Article
Subjects: SUDEP
cardiac arrhythmia
epilepsy
genetics
ion channels
Appears in Collections:Journal articles

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