Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy
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 sa...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/67555 |
| _version_ | 1811227803481276416 |
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| author | Shai Kellner Abeer Abbasi Ido Carmi Ronit Heinrich Tali Garin-Shkolnik Tova Hershkovitz Moshe Giladi Yoni Haitin Katrine M Johannesen Rikke Steensbjerre Møller Shai Berlin |
| author_facet | Shai Kellner Abeer Abbasi Ido Carmi Ronit Heinrich Tali Garin-Shkolnik Tova Hershkovitz Moshe Giladi Yoni Haitin Katrine M Johannesen Rikke Steensbjerre Møller Shai Berlin |
| author_sort | Shai Kellner |
| collection | DOAJ |
| description | 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 EC50, with G689S exhibiting the largest reductions observed for GRIN2B (~2000-fold). Moreover, variants multimerize with, and upregulate, GluN2Bwt-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. |
| first_indexed | 2024-04-12T09:47:55Z |
| format | Article |
| id | doaj.art-b7a463d386444368ab21bae7d74b7c3b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:47:55Z |
| publishDate | 2021-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-b7a463d386444368ab21bae7d74b7c3b2022-12-22T03:37:54ZengeLife Sciences Publications LtdeLife2050-084X2021-07-011010.7554/eLife.67555Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathyShai Kellner0Abeer Abbasi1Ido Carmi2Ronit Heinrich3Tali Garin-Shkolnik4Tova Hershkovitz5Moshe Giladi6Yoni Haitin7Katrine M Johannesen8Rikke Steensbjerre Møller9Shai Berlin10https://orcid.org/0000-0002-5153-4876Department of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelClalit health services, Tel Aviv, IsraelGenetics Institute, Rambam medical center, Haifa, IsraelDepartment of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense, DenmarkDepartment of Epilepsy Genetics and Personalized Treatment, the Danish Epilepsy Centre, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense, DenmarkDepartment of Neuroscience, Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelThe 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 EC50, with G689S exhibiting the largest reductions observed for GRIN2B (~2000-fold). Moreover, variants multimerize with, and upregulate, GluN2Bwt-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.https://elifesciences.org/articles/67555GRINencephalopathyligand binding domainde novo mutationloss of functionneurons |
| spellingShingle | Shai Kellner Abeer Abbasi Ido Carmi Ronit Heinrich Tali Garin-Shkolnik Tova Hershkovitz Moshe Giladi Yoni Haitin Katrine M Johannesen Rikke Steensbjerre Møller Shai Berlin Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy eLife GRIN encephalopathy ligand binding domain de novo mutation loss of function neurons |
| title | Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy |
| title_full | Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy |
| title_fullStr | Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy |
| title_full_unstemmed | Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy |
| title_short | Two de novo GluN2B mutations affect multiple NMDAR-functions and instigate severe pediatric encephalopathy |
| title_sort | two de novo glun2b mutations affect multiple nmdar functions and instigate severe pediatric encephalopathy |
| topic | GRIN encephalopathy ligand binding domain de novo mutation loss of function neurons |
| url | https://elifesciences.org/articles/67555 |
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