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.
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Change history
08 March 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41583-021-00449-5
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Acknowledgements
The preparation of this Review was supported by US Public Health Service grant R01 NS34509. The authors thank G. M. Lenk and L. L. Isom for helpful comments on the manuscript.
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Related links
Databases with information about patient variants. SCN1A: https://www.scn1a.net/
SCN2A: https://www.dropbox.com/s/gisihairans4dpa/SUP_SCN2A_TABLE_S1.xlsx?dl=0
SCN8A: https://scn8a.net
Glossary
- Loss-of-function (LOF) variants
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Complete loss-of-function (LOF) variants abolish channel function. They can also be partial, where a reduced level of normal channel function is retained.
- Poison exons
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Alternatively spliced exons that result in protein truncation, for example, due to the presence of an in-frame stop codon.
- Haploinsufficient
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A gene for which 50% of normal expression is insufficient and results in disease.
- Gain-of-function variant
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A missense variant with altered amino acid sequence that results in abnormal channel function.
- Modifier genes
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Unrelated genes whose expression can modify the severity of a disorder.
- Orthologues
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Evolutionarily corresponding genes in two species, for example mouse Scn1a and human SCN1A.
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Meisler, M.H., Hill, S.F. & Yu, W. Sodium channelopathies in neurodevelopmental disorders. Nat Rev Neurosci 22, 152–166 (2021). https://doi.org/10.1038/s41583-020-00418-4
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DOI: https://doi.org/10.1038/s41583-020-00418-4
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