TY - JOUR
T1 - Cardiac sodium channel mutations
T2 - Why so many phenotypes?
AU - Liu, Man
AU - Yang, Kai Chien
AU - Dudley, Samuel C.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Mutations of the cardiac sodium channel (Na v 1.5) 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 Na v 1.5 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.
AB - Mutations of the cardiac sodium channel (Na v 1.5) 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 Na v 1.5 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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U2 - 10.1038/nrcardio.2014.85
DO - 10.1038/nrcardio.2014.85
M3 - Review article
C2 - 24958080
AN - SCOPUS:84926104165
SN - 1759-5002
VL - 11
SP - 607
EP - 615
JO - Nature Reviews Cardiology
JF - Nature Reviews Cardiology
IS - 10
ER -