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 language | English (US) |
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Pages (from-to) | 905-913.e7 |
Journal | Neuron |
Volume | 99 |
Issue number | 5 |
DOIs | |
State | Published - Sep 5 2018 |
Funding
We are grateful to the families reported here. We thank F. Andermann, B. Bean, and members of the Clapham, Lehtinen, and Walsh labs for helpful discussions; B. Bean and D. Clapham for sharing electrophysiology equipment, M. Marcotrigiano, Y. Wu, and the Boston Children’s Hospital Small Animal Imaging Lab for MRI, E. Pollack and A. Nedder, and the Boston Children’s Hospital large animal facility, D. Gleason, J. Rodriguez, A. Malesz, R. Hu, for technical help, A. Pollen for sharing single cell sequencing data, J. Kearney for the WT SCN3A plasmid, D. Nguyen and L. Al-Gazali for assistance with clinical data. This work was supported by NIH 1F32NS100033801 (R.S.S.); the Erasmus MC Mrace project #104673 (G.M.S.M.); the Finnish Medical Society , Arvo and Lea Ylppö Foundation , and Finnish governmental subsidiaries TLK0278 (R.P.) and TRTR019 (O.S.); The Folkhälsan Research Foundation (A.-E.L.); Paul G. Allen Frontiers Program , and NIH R01NS032457 and R01NS035129 (C.A.W.), the New York Stem Cell Foundation (M.K.L.), and BCH IDDRC 1U54HD090255 . C.A.W. is an Investigator of the Howard Hughes Medical Institute. M.K.L. is a New York Stem Cell Foundation – Robertson Investigator.
Keywords
- Cortical Development
- Na1.1
- Na1.3
- Oromotor
- Outer Radial Glia
- Polymicrogyria
- SCN1A
- SCN3A
- Speech
- Voltage-Gated Sodium Channel (VGSC)
ASJC Scopus subject areas
- General Neuroscience