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Cardiac sodium channel mutations: why so many phenotypes?

Nature Reviews Cardiology volume 11, pages 607–615 (2014)Cite this article

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Abstract

Mutations of the cardiac sodium channel (Nav1.5) can induce gain or loss of channel function. Gain-of-function mutations can cause long QT syndrome type 3 and possibly atrial fibrillation, whereas loss-of-function mutations are associated with a variety of phenotypes, such as Brugada syndrome, cardiac conduction disease, sick sinus syndrome, and possibly dilated cardiomyopathy. The phenotypes produced by Nav1.5 mutations vary according to the direct effect of the mutation on channel biophysics, but also with age, sex, body temperature, and between regions of the heart. This phenotypic variability makes genotype–phenotype correlations difficult. In this Perspectives article, we propose that phenotypic variability not ascribed to mutation-dependent changes in channel function might be the result of additional modifiers of channel behaviour, such as other genetic variation and alterations in transcription, RNA processing, translation, post-translational modifications, and protein degradation. Consideration of these modifiers might help to improve genotype–phenotype correlations and lead to new therapeutic strategies.

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Figure 1: A schematic representation of the cardiac action potential with the major contributing cardiac ion channel currents.
Figure 2: The Nav1.5 channel is part of a macromolecular complex.
Figure 3: Mutations in SCN5A can produce various clinical phenotypes.
Figure 4: Examples of phenotypic variability in patients carrying an SCN5A mutation.
Figure 5: The lifecycle of cardiac Nav1.5 and potential phenotypic modifiers.

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Acknowledgements

K.-C.Y. is funded by an AHA Midwest Affiliation Postdoctoral Fellowship AHA13POST14380029. S.C.D. is funded by NIH grants RO1 HL104025, RO1 HL106592, and R41 HL112355; and a Veterans Affairs MERIT grant BX000859.

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Authors and Affiliations

  1. Warren Alpert Medical School, Brown University, 593 Eddy Street, APC730, Providence, 02903, RI, USA

    Man Liu, Kai-Chien Yang & Samuel C. Dudley Jr

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  1. Man Liu
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  2. Kai-Chien Yang
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  3. Samuel C. Dudley Jr
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Contributions

All the authors researched data for the article, contributed substantially to discussions of content, wrote the article, and reviewed/edited the manuscript before submission.

Corresponding author

Correspondence to Samuel C. Dudley Jr.

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Competing interests

S.C.D. is the inventor on patents or patent applications: SCN5A splice variants for use in methods relating to sudden cardiac death and need for implanted cardiac defibrillators (PCT/US2012/20564); SCN5A splicing factors and splice variants for use in diagnostic and prognostic methods (US 13/291,826); Modulation of sodium channels by nicotinamide adenine dinucleotide (US 8,003,324); Human sodium channel isoforms (US 11/707,882); Method for modulating or controlling sodium channel current by reactive oxygen species (US 12/929,786); Activation of the renin–angiotensin system (RAS) and sudden cardiac death (US 13/032,629); Modulation of sodium channels by nicotinamide adenine dinucleotide (US 13/067,953); and Method for detecting Brugada syndrome (US 61/786,882). S.C.D. founded a company called 3PrimeDx to commercialize a blood test for sudden death risk. The other authors declare no competing interests.

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Liu, M., Yang, KC. & Dudley, S. Cardiac sodium channel mutations: why so many phenotypes?. Nat Rev Cardiol 11, 607–615 (2014). https://doi.org/10.1038/nrcardio.2014.85

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