Elucidating structural role of disease-associated mutations in cardiac sodium channel Nav1.5

Abstract

Voltage-gated sodium (Nav) channels serve a central role in electrical excitability, with more than 1000 mutations in human Nav channels linked to various excitability disorders in heart, muscle, and brain. The genetic disruption of the cardiac sodium channel Nav1.5 has been identified as a major cause of various life-threatening cardiac disorders. In spite of the explosive growth of genomic data, many essential questions stand in the way of developing accurate diagnosis and selective therapy. For instance, at least 30 mutations are linked with both Gain-of-Function and Loss-of-Function diseases, but how the same mutations lead to both effects remains enigmatic.