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 Wit; Grazia M.S. Mancini; Laszlo Sztriha; Kiho Im; Dina Amrom; Eva Andermann; Ritva Paetau; Anna Elina Lehesjoki; Christopher A. Walsh; Maria K. Lehtinen

doi:10.1016/j.neuron.2018.07.052

Sodium Channel SCN3A (Na_V1.3) 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

Pharmacology

Research output: Contribution to journal › Article › peer-review

116 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 Na_V1.3. Pathogenic Na_V1.3 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 (Na_V1.1) 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 (Na_V1.3) in the developing human cerebral cortex, as well as a cortical malformation that can result from Na_V1.3 dysfunction.

Original language	English (US)
Pages (from-to)	905-913.e7
Journal	Neuron
Volume	99
Issue number	5
DOIs	https://doi.org/10.1016/j.neuron.2018.07.052
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

Access to Document

10.1016/j.neuron.2018.07.052

Cite this

Smith, R. S., Kenny, C. J., Ganesh, V., Jang, A., Borges-Monroy, R., Partlow, J. N., Hill, R. S., Shin, T., Chen, A. Y., Doan, R. N., Anttonen, A. K., Ignatius, J., Medne, L., Bönnemann, C. G., Hecht, J. L., Salonen, O., Barkovich, A. J., Poduri, A., Wilke, M., ... Lehtinen, M. K. (2018). Sodium Channel SCN3A (Na_V1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development. Neuron, 99(5), 905-913.e7. https://doi.org/10.1016/j.neuron.2018.07.052

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

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.",

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

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

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Smith, RS, Kenny, CJ, Ganesh, V, Jang, A, Borges-Monroy, R, Partlow, JN, Hill, RS, Shin, T, Chen, AY, Doan, RN, Anttonen, AK, Ignatius, J, Medne, L, Bönnemann, CG, Hecht, JL, Salonen, O, Barkovich, AJ, Poduri, A, Wilke, M, de Wit, MCY, Mancini, GMS, Sztriha, L, Im, K, Amrom, D, Andermann, E, Paetau, R, Lehesjoki, AE, Walsh, CA & Lehtinen, MK 2018, 'Sodium Channel SCN3A (Na_V1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development', Neuron, vol. 99, no. 5, pp. 905-913.e7. https://doi.org/10.1016/j.neuron.2018.07.052

TY - JOUR

T1 - Sodium Channel SCN3A (NaV1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development

AU - Smith, Richard S.

AU - Kenny, Connor J.

AU - Ganesh, Vijay

AU - Jang, Ahram

AU - Borges-Monroy, Rebeca

AU - Partlow, Jennifer N.

AU - Hill, R. Sean

AU - Shin, Taehwan

AU - Chen, Allen Y.

AU - Doan, Ryan N.

AU - Anttonen, Anna Kaisa

AU - Ignatius, Jaakko

AU - Medne, Livija

AU - Bönnemann, Carsten G.

AU - Hecht, Jonathan L.

AU - Salonen, Oili

AU - Barkovich, A. James

AU - Poduri, Annapurna

AU - Wilke, Martina

AU - de Wit, Marie Claire Y.

AU - Mancini, Grazia M.S.

AU - Sztriha, Laszlo

AU - Im, Kiho

AU - Amrom, Dina

AU - Andermann, Eva

AU - Paetau, Ritva

AU - Lehesjoki, Anna Elina

AU - Walsh, Christopher A.

AU - Lehtinen, Maria K.

PY - 2018/9/5

Y1 - 2018/9/5

N2 - 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.

AB - 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.

KW - Cortical Development

KW - Na1.1

KW - Na1.3

KW - Oromotor

KW - Outer Radial Glia

KW - Polymicrogyria

KW - SCN1A

KW - SCN3A

KW - Speech

KW - Voltage-Gated Sodium Channel (VGSC)

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DO - 10.1016/j.neuron.2018.07.052

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