Early onset epilepsy and sudden unexpected death in epilepsy with cardiac arrhythmia in mice carrying the early infantile epileptic encephalopathy 47 gain‐of‐function FHF1(FGF12) missense mutation

Abstract

Objective: Fibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel-binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain-of-function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice. Methods: The Arg52His mutation was introduced into fertilized eggs by CRISPR (clustered regularly interspaced short palindromic repeats) editing to generate Fhf1 R52H/F+ mice. Spontaneous epileptiform events in Fhf1 R52H/+ mice were assessed by cortical electroencephalography (EEG) and video monitoring. Basal heart rhythm and seizure-induced arrhythmia were recorded by electrocardiography. Modulation of cardiac sodium channel inactivation by FHF1B R52H protein was assayed by voltageclamp recordings of FHF-deficient mouse cardiomyocytes infected with adenoviruses expressing wild-type FHF1B or FHF1B R52H protein. Results: All Fhf1 R52H/+ mice experienced seizure or seizurelike episodes with lethal ending between 12 and 26 days of age. EEG recordings in 19-20-day-old mice confirmed sudden unexpected death in epilepsy (SUDEP) as severe tonic seizures

FGF12 is a novel component of the nucleolar NOLC1/TCOF1 ribosome biogenesis complex

“…FHFs are pleiotropic proteins whose dysregulation is associated with disorders of the nervous system, cardiac diseases and cancer [ 19 , 39 – 53 ]. The specificity of FHFs function appears to be largely determined by their subcellular localization.…”

Modulating effects of FGF12 variants on NaV1.2 and NaV1.6 being associated with developmental and epileptic encephalopathy and Autism spectrum disorder: A case series

“…This hypothesis is supported by the FGF12 mouse variant model fgf12 R52H/+ which suffers from spontaneous seizures and dies of sudden unexplained death in epilepsy (SUDEP) at around 16 days of age. 31 Veliskova and co-workers treated these mice with phenytoin, but the survival time was just marginally prolonged to about 19 days. 31 Another previous study showed the modifying effect of a hypomorphic variant in GABRA2 which increased seizure severity in mouse models carrying human SCN8A variants.…”

“… 31 Veliskova and co-workers treated these mice with phenytoin, but the survival time was just marginally prolonged to about 19 days. 31 Another previous study showed the modifying effect of a hypomorphic variant in GABRA2 which increased seizure severity in mouse models carrying human SCN8A variants. This suggests that GABRA2 could be a therapeutic target.…”

Noradrenergic pathway from the locus coeruleus to heart is implicated in modulating SUDEP

“…The mice were video recorded for offline analysis of the incidence of S-IRA, latency to AGSZs, duration of wild running, clonic seizures, tonic-clonic seizures, and seizure scores, as described previously. 35 , 36 , 37 To observe the incidence of death among DBA/1 mice as well as heart rate changes due to esmolol, the group of mice (n = 6) used to confirm S-IRA 24 h before the start of the experiment was pre-treated with esmolol (50 mg/kg, IP) without administration of atomoxetine and subjected to acoustic stimulation in the same manner. For DBA/1 mice in all of the different pre-treatment groups, ECG was performed before acoustic stimulation and after S-IRA.…”

“…The mice were video recorded for offline analysis of the incidence of S-IRA, latency to GSZs, duration of wild running, clonic seizures, tonic-clonic seizures, and seizure scores, as described previously. 35 , 36 , 37 For DBA/1 mice in all the different pre-treatment groups, ECG was performed before and after IP administration of PTZ.…”