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Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage‐gated sodium channel function
Author(s) -
Scala Marcello,
Efthymiou Stephanie,
Sultan Tipu,
De Waele Jolien,
Panciroli Marta,
Salpietro Vincenzo,
Maroofian Reza,
Striano Pasquale,
Van Petegem Filip,
Houlden Henry,
Bosmans Frank
Publication year - 2021
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16913
Subject(s) - sodium channel , epilepsy , medicine , depolarization , endocrinology , sodium channel blocker , encephalopathy , sodium , chemistry , psychiatry , organic chemistry
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.