SCN2A takes center stage again as an autism gene

SCN2A codes for the alpha-2 subunit of the voltage-gated sodium channel and its mutations are implicated in Benign Familial Neonatal-Infantile Seizures (BFNIS). As BFNIS are rare, SCN2A has served as a model for age-related epilepsies rather than an important gene in clinical practice.  SCN2A has pretty much shaped the concept of dysfunctions of the axon initial segment (AIS) as a core pathology of benign infantile epilepsies in the first year of life. Some studies suggest an interesting mechanism for the striking age-related pattern seen in BFNIS.

Now SCN2A appears in a novel context. Three new studies published in Nature last week used whole-exome sequencing to identify genes with de novo mutations implicated in autism[1,2,3]. Despite over 2000 patients sequenced only few genes were discovered and SCN2A stood out due to independent observations in a Yale led study by Sanders et al, independently confirming earlier hints implicating it in autism spectrum disorders.

Model of SCN2A

Model of about half of the ion channel SCN2A from Modbase based on a bacterial ion channel. Rendered by PyMol.

As of now it is unclear how mutations in SCN2A result in autism but it might be worth noting that the critical period for seizures in BFNIS overlaps with the time period in which neurodevelopmental dysregulations in autism are expected – the first year of life.

Epilepsy research is moving past ion channels to genes previously implicated SCN2A in autism (neurexins, neuroligins, CNTNAP2) and autism research is rediscovering ion channels (SCN1A, em>SCN2A). Time to recycle the equipment for electrophysiology of ion channels.

Ingo Helbig

Child Neurology Fellow and epilepsy genetics researcher at the Children’s Hospital of Philadelphia (CHOP), USA and Department of Neuropediatrics, Kiel, Germany

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