Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development

Richard S. Smith, Connor J. Kenny, Vijay Ganesh, Ahram Jang, Rebeca Borges-Monroy, Jennifer N. Partlow, R. Sean Hill, Taehwan Shin, Allen Y. Chen, Ryan N. Doan, Anna Kaisa Anttonen, Jaakko Ignatius, Livija Medne, Carsten G. Bönnemann, Jonathan L. Hecht, Oili Salonen, A. James Barkovich, Annapurna Poduri, Martina Wilke, Marie Claire Y. de WitGrazia M.S. Mancini, Laszlo Sztriha, Kiho Im, Dina Amrom, Eva Andermann, Ritva Paetau, Anna Elina Lehesjoki, Christopher A. Walsh*, Maria K. Lehtinen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel NaV1.3. Pathogenic NaV1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (NaV1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons. Smith et al. define a role for sodium channel SCN3A (NaV1.3) in the developing human cerebral cortex, as well as a cortical malformation that can result from NaV1.3 dysfunction.

Original languageEnglish (US)
Pages (from-to)905-913.e7
JournalNeuron
Volume99
Issue number5
DOIs
StatePublished - Sep 5 2018
Externally publishedYes

Keywords

  • Cortical Development
  • Na1.1
  • Na1.3
  • Oromotor
  • Outer Radial Glia
  • Polymicrogyria
  • SCN1A
  • SCN3A
  • Speech
  • Voltage-Gated Sodium Channel (VGSC)

ASJC Scopus subject areas

  • Neuroscience(all)

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