Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes

© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain..

Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, 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 3049 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 centre 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 receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1422 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 versus 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 readouts 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.

Errataetall:	CommentIn: Epilepsy Curr. 2023 Jan 18;23(2):118-120. - PMID 37122415
Medienart:	E-Artikel

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	Zur Gesamtaufnahme - volume:146
Enthalten in:	Brain : a journal of neurology - 146(2023), 3 vom: 01. März, Seite 923-934

Sprache:	Englisch

Beteiligte Personen:

Brünger, Tobias [VerfasserIn] Pérez-Palma, Eduardo [VerfasserIn] Montanucci, Ludovica [VerfasserIn] Nothnagel, Michael [VerfasserIn] Møller, Rikke S [VerfasserIn] Schorge, Stephanie [VerfasserIn] Zuberi, Sameer [VerfasserIn] Symonds, Joseph [VerfasserIn] Lemke, Johannes R [VerfasserIn] Brunklaus, Andreas [VerfasserIn] Traynelis, Stephen F [VerfasserIn] May, Patrick [VerfasserIn] Lal, Dennis [VerfasserIn]

Links:	Volltext

Themen:	Bioinformatics Epilepsy Genetics Ion channel Journal Article Neurodevelopmental disorder Receptors, N-Methyl-D-Aspartate Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Anmerkungen:	Date Completed 03.03.2023 Date Revised 28.10.2023 published: Print CommentIn: Epilepsy Curr. 2023 Jan 18;23(2):118-120. - PMID 37122415 Citation Status MEDLINE

doi:	10.1093/brain/awac305

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	NLM345539850