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Updated: Jun 13, 2025

Determination of the Relative Cell Surface and Total Expression of Recombinant Ion Channels Using Flow Cytometry
Published on: September 28, 2016
Mapping structural distribution and gating-property impacts of disease-associated mutations in voltage-gated sodium
Amin Akbari Ahangar1, Eslam Elhanafy1, Hayden Blanton1
1Department of Biomolecular Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA.
Abstract:
Thousands of voltage-gated sodium (Nav) channel variants contribute to a variety of disorders, including epilepsy, cardiac arrhythmia, and pain disorders. Yet, the effects of more variants remain unclear. The conventional gain-of-function (GoF) or loss-of-function (LoF) classifications are frequently employed to interpret mutations' effects and guide therapy for sodium channelopathies. Our study challenges this binary classification by analyzing 525 mutations associated with 34 diseases across 366 electrophysiology studies, revealing that diseases with similar GoF/LoF effects can stem from unique molecular mechanisms. Utilizing UniProt data, we mapped over 2,400 disease-associated missense mutations across Nav channels. This analysis pinpoints key mutation hotspots and maps patterns of gating-property impacts for the mutations, respectively, located around the selectivity filter, activation gate, fast inactivation region, and voltage-sensing domains. This study shows great potential to enhance prediction accuracy for mutational effects based on the structural context, paving the way for targeted drug design in precision medicine.
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