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Loss-of-function variants of SCN8A in intellectual disability without seizures.

Publication ,  Journal Article
Wagnon, JL; Barker, BS; Ottolini, M; Park, Y; Volkheimer, A; Valdez, P; Swinkels, MEM; Patel, MK; Meisler, MH
Published in: Neurol Genet
August 2017

OBJECTIVE: To determine the functional effect of SCN8A missense mutations in 2 children with intellectual disability and developmental delay but no seizures. METHODS: Genomic DNA was analyzed by next-generation sequencing. SCN8A variants were introduced into the Nav1.6 complementary DNA by site-directed mutagenesis. Channel activity was measured electrophysiologically in transfected ND7/23 cells. The stability of the mutant channels was assessed by Western blot. RESULTS: Both children were heterozygous for novel missense variants that altered conserved residues in transmembrane segments of Nav1.6, p.Gly964Arg in D2S6 and p.Glu1218Lys in D3S1. Both altered amino acids are evolutionarily conserved in vertebrate and invertebrate channels and are predicted to be deleterious. Neither was observed in the general population. Both variants completely prevented the generation of sodium currents in transfected cells. The abundance of Nav1.6 protein was reduced by the Glu1218Lys substitution. CONCLUSIONS: Haploinsufficiency of SCN8A is associated with cognitive impairment. These observations extend the phenotypic spectrum of SCN8A mutations beyond their established role in epileptic encephalopathy (OMIM#614558) and other seizure disorders. SCN8A should be considered as a candidate gene for intellectual disability, regardless of seizure status.

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Published In

Neurol Genet

DOI

ISSN

2376-7839

Publication Date

August 2017

Volume

3

Issue

4

Start / End Page

e170

Location

United States

Related Subject Headings

  • 3209 Neurosciences
  • 3202 Clinical sciences
  • 3105 Genetics
  • 1109 Neurosciences
  • 0604 Genetics
 

Citation

APA
Chicago
ICMJE
MLA
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Wagnon, J. L., Barker, B. S., Ottolini, M., Park, Y., Volkheimer, A., Valdez, P., … Meisler, M. H. (2017). Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet, 3(4), e170. https://doi.org/10.1212/NXG.0000000000000170
Wagnon, Jacy L., Bryan S. Barker, Matteo Ottolini, Young Park, Alicia Volkheimer, Purnima Valdez, Marielle E. M. Swinkels, Manoj K. Patel, and Miriam H. Meisler. “Loss-of-function variants of SCN8A in intellectual disability without seizures.Neurol Genet 3, no. 4 (August 2017): e170. https://doi.org/10.1212/NXG.0000000000000170.
Wagnon JL, Barker BS, Ottolini M, Park Y, Volkheimer A, Valdez P, et al. Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet. 2017 Aug;3(4):e170.
Wagnon, Jacy L., et al. “Loss-of-function variants of SCN8A in intellectual disability without seizures.Neurol Genet, vol. 3, no. 4, Aug. 2017, p. e170. Pubmed, doi:10.1212/NXG.0000000000000170.
Wagnon JL, Barker BS, Ottolini M, Park Y, Volkheimer A, Valdez P, Swinkels MEM, Patel MK, Meisler MH. Loss-of-function variants of SCN8A in intellectual disability without seizures. Neurol Genet. 2017 Aug;3(4):e170.

Published In

Neurol Genet

DOI

ISSN

2376-7839

Publication Date

August 2017

Volume

3

Issue

4

Start / End Page

e170

Location

United States

Related Subject Headings

  • 3209 Neurosciences
  • 3202 Clinical sciences
  • 3105 Genetics
  • 1109 Neurosciences
  • 0604 Genetics