Article (Scientific journals)
Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes
Brünger, Tobias; Pérez-Palma, Eduardo; Montanucci, Ludovica et al.
2023In Brain: a Journal of Neurology, 146 (3), p. 923-934
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Keywords :
genetics; epilepsy; neurodevelopmental disorders; ion channel; bioinformatics
Abstract :
[en] Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. Consequently, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated.We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion channel families. We collected and curated 3,049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12,546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures.We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis center and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate (NMDA) receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1,422 neurodevelopmental disorder pathogenic patient variants and 679 electrophysiological experiments, we show that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain vs. loss-of-channel function.In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional read-outs and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Brünger, Tobias
Pérez-Palma, Eduardo
Montanucci, Ludovica
Nothnagel, Michael
Møller, Rikke S.
Schorge, Stephanie
Zuberi, Sameer
Symonds, Joseph
Lemke, Johannes R.
Brunklaus, Andreas
Traynelis, Stephen F.
May, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Lal, Dennis
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Language :
Title :
Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes
Publication date :
01 March 2023
Journal title :
Brain: a Journal of Neurology
Publisher :
Oxford University Press, Oxford, United Kingdom
Volume :
Issue :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR16394868 - Epileptogenesis Of Genetic Epilepsies, 2021 (01/10/2021-...) - Alexander Skupin
Name of the research project :
Treat-ION, MechEPI-2
Funders :
FNR - Fonds National de la Recherche [LU]
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since 31 August 2022


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