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  • Nipavan Chiamvimonvat
    Correspondence
    Address reprint requests and correspondence: Dr Nipavan Chiamvimonvat, Department of Internal Medicine and Pharmacology, University of California, Davis, GBSF 6315, 451 Health Science Dr, Davis, CA 95616.
    Affiliations
    Department of Internal Medicine and Pharmacology, University of California, Davis, Davis, California
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Published:January 16, 2021DOI:https://doi.org/10.1016/j.hrthm.2021.01.012
      Loss-of-function variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are linked to cardiac arrhythmia and sudden death. Bouza et al (JCI Insight 2021;141776, PMID 33411695) demonstrated that β1 subunits are substrates for sequential regulated intramembrane proteolysis (RIP) by BACE1 and γ-secretase, resulting in the generation of a soluble intracellular domain (ICD) that is translocated to the nucleus. The authors used RNA sequencing to identify a subset of genes that are downregulated by β1-ICD overexpression but are upregulated in Scn1b null cardiac tissue. The authors conclude that human disease variants resulting in SCN1B loss of function may cause transcriptional dysregulation that contributes to altered excitability, providing a novel link between RIP-excitation coupling to the multifunctionality of sodium channel β1 subunits.
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