Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy.

Autor: Kellner S; Department of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Abbasi A; Department of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Carmi I; Department of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Heinrich R; Department of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel., Garin-Shkolnik T; Clalit health services, Tel Aviv, Israel., Hershkovitz T; Genetics Institute, Rambam medical center, Haifa, Israel., Giladi M; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Haitin Y; Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Johannesen KM; Department of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark.; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark., Steensbjerre Møller R; Department of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark.; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark., Berlin S; Department of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Jazyk: angličtina
Zdroj: ELife [Elife] 2021 Jul 02; Vol. 10. Date of Electronic Publication: 2021 Jul 02.
DOI: 10.7554/eLife.67555
Abstrakt: The N-methyl-D-aspartate receptors (NMDARs; GluNRS) are glutamate receptors, commonly located at excitatory synapses. Mutations affecting receptor function often lead to devastating neurodevelopmental disorders. We have identified two toddlers with different heterozygous missense mutations of the same, and highly conserved, glycine residue located in the ligand-binding-domain of GRIN2B : G689C and G689S. Structure simulations suggest severely impaired glutamate binding, which we confirm by functional analysis. Both variants show three orders of magnitude reductions in glutamate EC 50 , with G689S exhibiting the largest reductions observed for GRIN2B (~2000-fold). Moreover, variants multimerize with, and upregulate, GluN2B wt -subunits, thus engendering a strong dominant-negative effect on mixed channels. In neurons, overexpression of the variants instigates suppression of synaptic GluNRs. Lastly, while exploring spermine potentiation as a potential treatment, we discovered that the variants fail to respond due to G689's novel role in proton-sensing. Together, we describe two unique variants with extreme effects on channel function. We employ protein-stability measures to explain why current (and future) LBD mutations in GluN2B primarily instigate Loss-of-Function.
Competing Interests: SK, AA, IC, RH, TG, TH, MG, YH, KJ, RS, SB No competing interests declared
(© 2021, Kellner et al.)
Databáze: MEDLINE
Externí odkaz: