Universität zu Köln

Brunger, Tobias, Perez-Palma, Eduardo, Montanucci, Ludovica, Nothnagel, Michael, Moller, Rikke S., Schorge, Stephanie ORCID: 0000-0003-1541-5148, Zuberi, Sameer ORCID: 0000-0002-4489-4697, Symonds, Joseph ORCID: 0000-0002-2141-4216, Lemke, Johannes R., Brunklaus, Andreas ORCID: 0000-0002-7728-6903, Traynelis, Stephen F., May, Patrick ORCID: 0000-0001-8698-3770 and Lal, Dennis (2023). Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes. Brain, 146 (3). S. 923 - 935. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

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 5 angstrom 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. Brunger et al. set out to systematically identify biological features associated with variant pathogenicity across all major ion-channel families. They show that the features identified are associated with molecular readouts and clinical phenotypes in patients with voltage-gated sodium channel and NMDA receptor-associated neurodevelopmental disorders.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Brunger, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Perez-Palma, Eduardo UNSPECIFIED UNSPECIFIED UNSPECIFIED Montanucci, Ludovica UNSPECIFIED UNSPECIFIED UNSPECIFIED Nothnagel, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Moller, Rikke S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schorge, Stephanie UNSPECIFIED orcid.org/0000-0003-1541-5148 UNSPECIFIED Zuberi, Sameer UNSPECIFIED orcid.org/0000-0002-4489-4697 UNSPECIFIED Symonds, Joseph UNSPECIFIED orcid.org/0000-0002-2141-4216 UNSPECIFIED Lemke, Johannes R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunklaus, Andreas UNSPECIFIED orcid.org/0000-0002-7728-6903 UNSPECIFIED Traynelis, Stephen F. UNSPECIFIED UNSPECIFIED UNSPECIFIED May, Patrick UNSPECIFIED orcid.org/0000-0001-8698-3770 UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-692937
DOI:	10.1093/brain/awac305
Journal or Publication Title:	Brain
Volume:	146
Number:	3
Page Range:	S. 923 - 935
Date:	2023
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPILEPTIC ENCEPHALOPATHY; MUTATION; RECEPTORS; SPECTRUM; GRIN2A Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69293