Sodium channelopathies in neurodevelopmental disorders

Abstract

The voltage-gated sodium channel α-subunit genes comprise a highly conserved gene family. Mutations of three of these genes, SCN1A, SCN2A and SCN8A, are responsible for a significant burden of neurological disease. Recent progress in identification and functional characterization of patient variants is generating new insights and novel approaches to therapy for these devastating disorders. Here we review the basic elements of sodium channel function that are used to characterize patient variants. We summarize a large body of work using global and conditional mouse mutants to characterize the in vivo roles of these channels. We provide an overview of the neurological disorders associated with mutations of the human genes and examples of the effects of patient mutations on channel function. Finally, we highlight therapeutic interventions that are emerging from new insights into mechanisms of sodium channelopathies.

Figure 1.. Evolutionary conservation of human sodium channel genes.

(A) Chromosomal locations of human voltage-gated sodium channel genes. The channels with high expression in the adult CNS (red) are covered in this review. (B) The voltage-gated sodium channel α subunit is composed of four transmembrane domains separated by intracellular loops. TM, transmembrane segments; b, N-terminus; c, cytoplasmic loop 1; d, cytoplasmic loop 2; e, inactivation gate; f, proximal half of C-terminus; g, distal half of C-terminus. (C) Percent conservation of amino acid sequence in the protein domains of SCN1A (Nav1.1), SCN2A (Nav1.2), and SCN8A (Nav1.6). Labels refer to domains in panel B. (D). Examples of regions of high sequence conservation in transmembrane segment DIS4 (left) and around the 9 residue ankyrin binding motif (right) . Dots represent amino acid identity.

Figure 2.. Channel properties frequently used to characterize patient mutations.

A, peak and persistent current. B, voltage dependence of channel activation. C, voltage dependence of channel inactivation. D, resurgent current. Vertical lines in B and C mark the voltage at which 50% of channels are active.

Figure 3.. Functional effects of patient mutations in SCN1A, SCN2A and SCN3A.

Representative examples adapted from the indicated publications, which contain experimental details. A. The Dravet Syndrome mutation p.S259R in SCN1A causes complete loss of channel function . B. The inherited variant p.R1648H in SCN1A in a family with GEFS+ causes increased persistent current . C. p.P1622S in SCN2A in a patient with late-onset DEE causes a hyperpolarizing shift in the voltage dependence of inactivation . D. p.L1653V in SCN2A in a family with benign familial neonatal-infantile seizures (BFNIS) causes rapid channel activation . E. p.R937H in SCN2A in a patient with autism spectrum disorder (ASD) causes loss of channel function . F. p.A263V in SCN2A in a patient with episodic ataxia causes increased persistent current . G. The mutation p.T767I in SCN8A in a patient with DEE causes premature channel activation . H. De novo mutation p.R1872W in SCN8A in a patient with DEE causes delayed channel inactivation . I. De novo mutation p.N1768D in SCN8A in a patient with DEE causes elevated resurgent current .

Figure 4.. Electrophysiological and cellular mechanisms underlying seizures in an in vivo mouse model of human sodium channelopathy.

The de novo mutation SCN8A-p.Arg1768Asp was identified in a child with DEE. Functional effects include impaired inactivation, elevated persistent current and elevated resurgent current . The altered biophysical properties of SCN8A result in elevated neuronal activity at the cellular level. A. In response to electrical stimulation, cultured hippocampal neurons transfected with the mutant channel generate more action potentials than cells transfected with wildtype channel . B. Slice recordings from Scn8a^N1768D/+ knock-in mice demonstrate spontaneous firing of hippocampal CA1 neurons . Spontaneous firing is not seen in layer 2/3 cortical neurons from the same mice. C. Enterorhinal cortex neurons from the knock-in mouse exhibit burst firing after synaptic stimulation .