Scn3a, encoding the voltage-gated sodium channel subunit Nav1.3, is crucial for the initiation and propagation of action potentials in the central nervous system [2]. Voltage-gated sodium channels are essential for neural network activity, and Scn3a is one of the genes encoding the α subunits of these channels [2].

Pathogenic variants in Scn3a cause severe childhood-onset epilepsy and malformation of cortical development. Most patients with such variants have treatment-resistant epilepsy starting in the first year of life and severe or profound developmental delay [1]. Many also exhibit malformations of cortical development. Pathogenic missense variants often display gain-of channel function, with increased persistent current and/or a left-ward shift in voltage dependence of activation, especially those associated with cortical malformations [1]. Loss-of-function SCN3A mutations, such as the L247P variant, may also lead to increased seizure susceptibility. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) showed increased susceptibility to electroconvulsive and chemiconvulsive induced seizures, along with deficits in locomotor activity and motor learning [3].

In conclusion, Scn3a is vital for normal neural function. Its dysfunction, whether through gain-or loss-of-function mutations, is closely associated with epilepsy and neurodevelopmental disorders. Studies on Scn3a mutant mouse models have provided insights into how Scn3a loss-of-function can contribute to increased seizure susceptibility and other behavioral deficits, helping to understand the pathogenesis of related diseases [1,3].

References:

1. Zaman, Tariq, Helbig, Katherine L, Clatot, Jérôme, Fry, Andrew E, Goldberg, Ethan M. 2020. SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation. In Annals of neurology, 88, 348-362. doi:10.1002/ana.25809. https://pubmed.ncbi.nlm.nih.gov/32515017/

2. Barbieri, Raffaella, Nizzari, Mario, Zanardi, Ilaria, Pusch, Michael, Gavazzo, Paola. 2023. Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders. In Life (Basel, Switzerland), 13, . doi:10.3390/life13051191. https://pubmed.ncbi.nlm.nih.gov/37240836/

3. Lamar, Tyra, Vanoye, Carlos G, Calhoun, Jeffrey, Escayg, Andrew, Kearney, Jennifer A. 2017. SCN3A deficiency associated with increased seizure susceptibility. In Neurobiology of disease, 102, 38-48. doi:10.1016/j.nbd.2017.02.006. https://pubmed.ncbi.nlm.nih.gov/28235671/