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

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

  • Neuron. 2018 Sep 5;99(5):905-913.e7. doi: 10.1016/j.neuron.2018.07.052.
Richard S Smith 1,  Connor J Kenny 1,  Vijay Ganesh 1,  Ahram Jang 2,  Rebeca Borges-Monroy 1,  Jennifer N Partlow 1,  R Sean Hill 1,  Taehwan Shin 1,  Allen Y Chen 1,  Ryan N Doan 1,  Anna-Kaisa Anttonen 3,  Jaakko Ignatius 4,  Livija Medne 5,  Carsten G Bönnemann 5,  Jonathan L Hecht 6,  Oili Salonen 7,  A James Barkovich 8,  Annapurna Poduri 9,  Martina Wilke 10,  Marie Claire Y de Wit 11,  Grazia M S Mancini 10,  Laszlo Sztriha 12,  Kiho Im 13,  Dina Amrom 14,  Eva Andermann 14,  Ritva Paetau 15,  Anna-Elina Lehesjoki 3,  Christopher A Walsh 16,  Maria K Lehtinen 17
Affiliations

Affiliations

  • 1 Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
  • 3 The Folkhälsan Institute of Genetics, 00290 Helsinki, Finland; Medical and Clinical Genetics, Neuroscience Center and Research Programs Unit, Molecular Neurology, 00014, University of Helsinki, Helsinki, Finland.
  • 4 Department of Clinical Genetics, Turku University Hospital, Turku, 20521, Finland.
  • 5 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 6 Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • 7 Medical Imaging Center, Radiology, University of Helsinki and Helsinki University Hospital, 00029 HUS, Helsinki, Finland.
  • 8 Benioff Children's Hospital, Departments of Radiology, Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, CA 94117, USA.
  • 9 Department of Neurology, Boston Children's Hospital and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
  • 10 Department of Clinical Genetics, Erasmus MC Rotterdam 3015CN, Netherlands.
  • 11 Neurogenetics Joint Clinic in Sophia Children's Hospital, Erasmus MC Rotterdam 3015CN, Netherlands.
  • 12 Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
  • 13 Division of Newborn Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 14 Neurogenetics Unit and Epilepsy Research Group, Montreal Neurological Institute and Hospital; and the Departments of Neurology & Neurosurgery and Human Genetics, McGill University, Montreal, QC H3A 2B4, Canada.
  • 15 Children's Hospital, University of Helsinki and Helsinki University Hospital, 00029 HUS, Helsinki, Finland.
  • 16 Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
  • 17 Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 30146301 DOI: 10.1016/j.neuron.2018.07.052
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.

Keywords

Cortical Development; Na(V)1.1; Na(V)1.3; Oromotor; Outer Radial Glia; Polymicrogyria; SCN1A; SCN3A; Speech; Voltage-Gated Sodium Channel (VGSC).

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