Association of rare missense variants in the second intracellular loop of Na v 1.7 sodium channels with familial autism

M. Rubinstein, A. Patowary, I. B. Stanaway, E. McCord, R. R. Nesbitt, M. Archer, T. Scheuer, D. Nickerson, W. H. Raskind, E. M. Wijsman, R. Bernier, W. A. Catterall*, Z. Brkanac

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel Na V 1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that Na V 1.7 C1143F exhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of Na V 1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, although this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. Although the involvement of the SCN1A and SCN2A genes encoding Na V 1.1 and Na V 1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss-of-function of Na V 1.7 channels in the etiology of rare familial ASD.

Original languageEnglish
Pages (from-to)231-239
Number of pages9
JournalMolecular Psychiatry
Issue number2
StatePublished - 1 Feb 2018


FundersFunder number
NIMH Center for Collaborative Genomic Research on Mental Disorders
National Institutes of Health240243
National Institute of Mental Health
National Institute of Neurological Disorders and StrokeR01 MH092367, R01NS025704
Simons Foundation


    Dive into the research topics of 'Association of rare missense variants in the second intracellular loop of Na v 1.7 sodium channels with familial autism'. Together they form a unique fingerprint.

    Cite this