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Gene variant effects across sodium channelopathies predict function and guide precision therapy.

Brunklaus, A; Feng, T; Brünger, T; Perez-Palma, E; Heyne, H; Matthews, E; Semsarian, C; Symonds, JD; Zuberi, SM; Lal, D; et al. Brunklaus, A; Feng, T; Brünger, T; Perez-Palma, E; Heyne, H; Matthews, E; Semsarian, C; Symonds, JD; Zuberi, SM; Lal, D; Schorge, S (2022) Gene variant effects across sodium channelopathies predict function and guide precision therapy. Brain, 145 (12). pp. 4275-4286. ISSN 1460-2156 https://doi.org/10.1093/brain/awac006
SGUL Authors: Matthews, Emma Louise

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Abstract

Pathogenic variants in the voltage-gated sodium channel gene family lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function. Therapeutic strategy is likely to depend on functional effect. Experimental studies offer important insights into channel function but are resource intensive and only performed in a minority of cases. Given the evolutionarily conserved nature of the sodium channel genes, we investigated whether similarities in biophysical properties between different voltage-gated sodium channels can predict function and inform precision treatment across sodium channelopathies. We performed a systematic literature search identifying functionally assessed variants in any of the nine voltage-gated sodium channel genes until 28 April 2021. We included missense variants that had been electrophysiologically characterized in mammalian cells in whole-cell patch-clamp recordings. We performed an alignment of linear protein sequences of all sodium channel genes and correlated variants by their overall functional effect on biophysical properties. Of 951 identified records, 437 sodium channel-variants met our inclusion criteria and were reviewed for functional properties. Of these, 141 variants were epilepsy-associated (SCN1/2/3/8A), 79 had a neuromuscular phenotype (SCN4/9/10/11A), 149 were associated with a cardiac phenotype (SCN5/10A) and 68 (16%) were considered benign. We detected 38 missense variant pairs with an identical disease-associated variant in a different sodium channel gene. Thirty-five out of 38 of those pairs resulted in similar functional consequences, indicating up to 92% biophysical agreement between corresponding sodium channel variants (odds ratio = 11.3; 95% confidence interval = 2.8 to 66.9; P < 0.001). Pathogenic missense variants were clustered in specific functional domains, whereas population variants were significantly more frequent across non-conserved domains (odds ratio = 18.6; 95% confidence interval = 10.9-34.4; P < 0.001). Pore-loop regions were frequently associated with loss-of-function variants, whereas inactivation sites were associated with gain-of-function (odds ratio = 42.1, 95% confidence interval = 14.5-122.4; P < 0.001), whilst variants occurring in voltage-sensing regions comprised a range of gain- and loss-of-function effects. Our findings suggest that biophysical characterisation of variants in one SCN-gene can predict channel function across different SCN-genes where experimental data are not available. The collected data represent the first gain- versus loss-of-function topological map of SCN proteins indicating shared patterns of biophysical effects aiding variant analysis and guiding precision therapy. We integrated our findings into a free online webtool to facilitate functional sodium channel gene variant interpretation (http://SCN-viewer.broadinstitute.org).

Item Type: Article
Additional Information: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Keywords: SCN1A, SCN2A, SCN4A, SCN5A, SCN8A, Animals, Channelopathies, Peripheral Nervous System Diseases, Voltage-Gated Sodium Channels, Epilepsy, Phenotype, Mammals, SCN1A, SCN2A, SCN4A, SCN5A, SCN8A, SCN1A, SCN2A, SCN4A, SCN5A, SCN8A, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Brain
ISSN: 1460-2156
Language: eng
Dates:
DateEvent
19 December 2022Published
10 December 2021Accepted
Publisher License: Creative Commons: Attribution-Noncommercial 4.0
Projects:
Project IDFunderFunder ID
MR/V037838/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 35037686
Web of Science ID: WOS:000852457900001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/114247
Publisher's version: https://doi.org/10.1093/brain/awac006

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