The comparative structural analysis of Na v 1.1 and Na v 1.5 establishes a framework for understanding structure-function relationships of disease variants in sodium channelopathies.
Structural mapping of shared Na v mutation loci may refine variant interpretation; leaves open functional validation and therapeutic translation in epilepsy and cardiac channelopathies.
Significance Na v 1.1 is a major Na v subtype in the brain. Up to 900 nonsense and missense mutations in SCN1A , the coding gene for Na v 1.1, have been identified in patients with epilepsy syndromes. Here, we report the cryo-EM structure of the human Na v 1.1–β4 complex. Comparative structural analysis of hundreds of missense disease mutations in Na v 1.1 and Na v 1.5, whose structure is reported in the accompanying paper, reveals 70 loci that are common in these two channels. Several clusters, defined as the mutational hotspots, are identified and generally classified as the structural mutations and functional mutations. Our comparative structural analyses establish a framework for structure–function relationship dissection of Na v disease variants and will facilitate development of precision medicine for various sodium channelopathies.
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Pan et al. (2021) studied this question.
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