Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function

Autor: Pasquale Striano, Frank Bosmans, Vincenzo Salpietro, Jolien De Waele, Filip Van Petegem, Marta Panciroli, Marcello Scala, Stephanie Efthymiou, Reza Maroofian, Tipu Sultan, Henry Houlden
Rok vydání: 2021
Předmět:
0301 basic medicine
Refractory seizures
Male
Models
Molecular
Drug Resistant Epilepsy
Voltage-Gated Sodium Channels
developmental and epileptic encephalopathy
early infantile epileptic encephalopathy 52
EIEE52
SCN1B
voltage-gated sodium channel
Child
Child
Preschool
Chromosome Mapping
DNA
Electroencephalography
Exome
Female
Genetic Variation
Humans
Infant
Mutation
Missense
Pedigree
Seizures
Spasms
Infantile
Voltage-Gated Sodium Channel beta-1 Subunit
Infantile
Spasms
0302 clinical medicine
Models
Epileptic encephalopathy
Depolarization
Nav channel
Neurology
medicine.medical_specialty
Article
03 medical and health sciences
Internal medicine
medicine
Preschool
business.industry
Sodium channel
Molecular
Early Infantile Epileptic Encephalopathy
030104 developmental biology
Endocrinology
Mutation
Neurology (clinical)
Infantile onset
Missense
business
030217 neurology & neurosurgery
Zdroj: Epilepsia
ISSN: 1528-1167
Popis: We identified nine patients from four unrelated families harboring three biallelic variants in SCN1B (NM_001037.5: c.136C>T; p.[Arg46Cys], c.178C>T; p.[Arg60Cys], and c.472G>A; p.[Val158Met]). All subjects presented with early infantile epileptic encephalopathy 52 (EIEE52), a rare, severe developmental and epileptic encephalopathy featuring infantile onset refractory seizures followed by developmental stagnation or regression. Because SCN1B influences neuronal excitability through modulation of voltage-gated sodium (Na(V)) channel function, we examined the effects of human SCN1B(R46C) (β1(R46C)), SCN1B(R60C) (β1(R60C)), and SCN1B(V158M) (β1(V158M)) on the three predominant brain Na(V) channel subtypes Na(V)1.1 (SCN1A), Na(V)1.2 (SCN2A), and Na(V)1.6 (SCN8A). We observed a shift toward more depolarizing potentials of conductance–voltage relationships (Na(V)1.2/β1(R46C), Na(V)1.2/β1(R60C), Na(V)1.6/β1(R46C), Na(V)1.6/β1(R60C), and Na(V)1.6/β1(V158M)) and channel availability (Na(V)1.1/β1(R46C), Na(V)1.1/β1(V158M), Na(V)1.2/β1(R46C), Na(V)1.2/β1(R60C), and Na(V)1.6/β1(V158M)), and detected a slower recovery from fast inactivation for Na(V)1.1/β1(V158M). Combined with modeling data indicating perturbation-induced structural changes in β1, these results suggest that the SCN1B variants reported here can disrupt normal Na(V) channel function in the brain, which may contribute to EIEE52.
Databáze: OpenAIRE
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