Universität zu Köln

Brunklaus, Andreas ORCID: 0000-0002-7728-6903, Feng, Tony, Brunger, Tobias, Perez-Palma, Eduardo, Heyne, Henrike ORCID: 0000-0001-9893-3850, Matthews, Emma, Semsarian, Christopher, Symonds, Joseph D., Zuberi, Sameer M., Lal, Dennis and Schorge, Stephanie ORCID: 0000-0003-1541-5148 (2022). Gene variant effects across sodium channelopathies predict function and guide precision therapy. Brain, 145 (12). S. 4275 - 4287. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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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:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Brunklaus, Andreas UNSPECIFIED orcid.org/0000-0002-7728-6903 UNSPECIFIED Feng, Tony UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunger, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Perez-Palma, Eduardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Heyne, Henrike UNSPECIFIED orcid.org/0000-0001-9893-3850 UNSPECIFIED Matthews, Emma UNSPECIFIED UNSPECIFIED UNSPECIFIED Semsarian, Christopher UNSPECIFIED UNSPECIFIED UNSPECIFIED Symonds, Joseph D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zuberi, Sameer M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Schorge, Stephanie UNSPECIFIED orcid.org/0000-0003-1541-5148 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-694135
DOI:	10.1093/brain/awac006
Journal or Publication Title:	Brain
Volume:	145
Number:	12
Page Range:	S. 4275 - 4287
Date:	2022
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SEVERE MYOCLONIC EPILEPSY; EXTREME PAIN DISORDER; CLINICAL SPECTRUM; CHANNEL DEFECTS; MUTATIONS; MEXILETINE; MEDICINE; GAIN; NOMENCLATURE; SYSTEMS Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69413