Rare dysfunctional SCN2A variants are associated with malformation of cortical development

Jérôme Clatot, Christopher H. Thompson, Susan Sotardi, Jinan Jiang, Marina Trivisano, Simona Balestrini, D. Isum Ward, Natalie Ginn, Brunetta Guaragni, Laura Malerba, Angeliki Vakrinou, Mia Sherer, Ingo Helbig, Ala Somarowthu, Sanjay M. Sisodiya, Roy Ben-Shalom, Renzo Guerrini, Nicola Specchio, Alfred L. George, Ethan M. Goldberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: SCN2A encodes the voltage-gated sodium (Na+) channel α subunit NaV1.2, which is important for the generation and forward and back propagation of action potentials in neurons. Genetic variants in SCN2A are associated with a spectrum of neurodevelopmental disorders. However, the mechanisms whereby variation in SCN2A leads to disease remains incompletely understood, and the full spectrum of SCN2A-related disorders may not be fully delineated. Methods: Here, we identified seven de novo heterozygous variants in SCN2A in eight individuals with developmental and epileptic encephalopathy (DEE) accompanied by prominent malformation of cortical development (MCD). We characterized the electrophysiological properties of Na + currents in human embryonic kidney (HEK) cells transfected with the adult (A) or neonatal (N) isoform of wild-type (WT) and variant NaV1.2 using manual and automated whole-cell voltage clamp recording. Results: The neonatal isoforms of all SCN2A variants studied exhibit gain of function (GoF) with a large depolarized shift in steady-state inactivation, creating a markedly enhanced window current common across all four variants tested. Computational modeling demonstrated that expression of the NaV1.2-p.Met1770Leu-N variant in a developing neocortical pyramidal neuron results in hyperexcitability. Significance: These results support expansion of the clinical spectrum of SCN2A-related disorders and the association of genetic variation in SCN2A with MCD, which suggests previously undescribed roles for SCN2A in fetal brain development.

Original languageEnglish (US)
JournalEpilepsia
DOIs
StateAccepted/In press - 2024

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) R01 NS119977 to E.M.G. and U54 NS108874 to A.L.G.; Current Research 2023 of the Italian Ministry of Health (to R.G. and S.B.); Ministry of University and Research (MIUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) (to R.G. and S.B.); Brain Optical Mapping by Fondazione CARIFI (to R.G.); and DECODEE Call Health 2018 of the Tuscany Region (to R.G.). We would like to thank the patients enrolled in the study and their families for participation in research, referring providers and clinicians involved in the care of these patients, as well as Leah Schust for her leadership of the FamilieSCN2A Foundation and involvement in the project.

Keywords

  • Nav1.2
  • SCN2A
  • developmental and epileptic encephalopathy
  • malformation of cortical development
  • voltage-gated sodium channel

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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