Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain

Lindsay Liang, Siavash Fazel Darbandi, Sirisha Pochareddy, Forrest O. Gulden, Michael C. Gilson, Brooke K. Sheppard, Atehsa Sahagun, Joon Yong An, Donna M. Werling, John L.R. Rubenstein, Nenad Sestan, Kevin J. Bender, Stephan J. Sanders

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


Background: Genetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of individual exons in the developing human brain. Methods: RNA-seq data from 783 human brain samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples. Results: In the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A, a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories. Conclusions: Exon usage in SCN1A, SCN2A, SCN3A, and SCN8A changes dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.

Original languageEnglish
Article number135
JournalGenome Medicine
Issue number1
Publication statusPublished - 2021 Dec

Bibliographical note

Funding Information:
J.L.R.R. is cofounder, stockholder, and currently on the scientific board of Neurona, a company studying the potential therapeutic use of interneuron transplantation. S.J.S. receives research funding from BioMarin Pharmaceutical Inc. The remaining authors declare that they have no competing interests.

Funding Information:
This work was supported by funding provided by the Simons Foundation Autism Research Initiative (SFARI) grants 574598 (to S.J.S.), 647371 (to S.J.S.), 629287 (to K.J.B.), and 513133 (to K.J.B.), the National Institute for Mental Health (NIMH) grants: R01 MH111662 (to S.J.S.), U01 MH122681 (to S.J.S.), R01 MH125978 (to K.J.B.), U01 MH122678 (to N.S.), P50 MH106934 (to N.S.), R01 MH109904 (to N.S.), R01 MH110926 (to N.S.), and U01 MH116488 (to N.S.), the National Institute of Neurological Disorders and Stroke (NINDS) grant: R01 NS099099 (to J.L.R.R.), and the National Research Foundation of Korea: NRF-2020R1C1C1003426 (to J.Y.A.) and NRF-2017M3C7A1026959 (to J.Y.A.). Data used in this study were generated as part of the PsychENCODE Consortium, supported by U01MH103339, U01MH103365, U01MH103392, U01MH103340, U01MH103346, R01MH105472, R01MH094714, R01MH105898, R21MH102791, R21MH105881, R21MH103877, and P50MH106934 awarded to Schahram Akbarian (Icahn School of Medicine at Mount Sinai), Gregory Crawford (Duke), Stella Dracheva (Icahn School of Medicine at Mount Sinai), Peggy Farnham (USC), Mark Gerstein (Yale), Daniel Geschwind (UCLA), Thomas M. Hyde (LIBD), Andrew Jaffe (LIBD), James A. Knowles (USC), Chunyu Liu (UIC), Dalila Pinto (Icahn School of Medicine at Mount Sinai), Nenad Sestan (Yale), Pamela Sklar (Icahn School of Medicine at Mount Sinai), Matthew State (UCSF), Patrick Sullivan (UNC), Flora Vaccarino (Yale), Sherman Weissman (Yale), Kevin White (UChicago), and Peter Zandi (JHU).

Publisher Copyright:
© 2021, The Author(s).


  • Autism spectrum disorder
  • Developmental delay
  • Epileptic encephalopathy
  • Exon 5A
  • Exon 5N
  • Intellectual disability
  • Isoform
  • Seizures
  • Splicing
  • Voltage-gated sodium channel

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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