Scala, M;
Efthymiou, S;
Sultan, T;
De Waele, J;
Panciroli, M;
Salpietro, V;
Maroofian, R;
... Bosmans, F; + view all
(2021)
Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function.
Epilepsia
, 62
(6)
e82-e87.
10.1111/epi.16913.
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Abstract
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 (NaV ) channel function, we examined the effects of human SCN1BR46C (β1R46C ), SCN1BR60C (β1R60C ), and SCN1BV158M (β1V158M ) on the three predominant brain NaV channel subtypes NaV 1.1 (SCN1A), NaV 1.2 (SCN2A), and NaV 1.6 (SCN8A). We observed a shift toward more depolarizing potentials of conductance-voltage relationships (NaV 1.2/β1R46C , NaV 1.2/β1R60C , NaV 1.6/β1R46C , NaV 1.6/β1R60C , and NaV 1.6/β1V158M ) and channel availability (NaV 1.1/β1R46C , NaV 1.1/β1V158M , NaV 1.2/β1R46C , NaV 1.2/β1R60C , and NaV 1.6/β1V158M ), and detected a slower recovery from fast inactivation for NaV 1.1/β1V158M . Combined with modeling data indicating perturbation-induced structural changes in β1, these results suggest that the SCN1B variants reported here can disrupt normal NaV channel function in the brain, which may contribute to EIEE52.
| Type: | Article |
|---|---|
| Title: | Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/epi.16913 |
| Publisher version: | http://dx.doi.org/10.1111/epi.16913 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | SCN1B, EIEE52, developmental and epileptic encephalopathy, early infantile epileptic encephalopathy 52, voltage-gated sodium channel |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10127824 |
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