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

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*

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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 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.

OriginalsprogEngelsk
Artikelnummere67555
TidsskrifteLife
Vol/bind10
Antal sider28
ISSN2050-084X
DOI
StatusUdgivet - 2. jul. 2021

Bibliografisk note

Funding Information:
We thank the GRIN disorder research foundation (GDRF) for providing clinical data on the G689C patient and for the GRIN families. The research submitted is in partial fulfillment for a doctoral degree for SK and magister’s degree for AA. Funding— Support was provided by the Israel Science Foundation (SB; 1096/17) and by TEVA pharmaceuticals scholarship (SK; PR783187).

Funding Information:
We thank the GRIN disorder research foundation (GDRF) for providing clinical data on the G689C patient and for the GRIN families. The research submitted is in partial fulfillment for a doctoral degree for SK and magister?s degree for AA. Funding? Support was provided by the Israel Science Foundation (SB; 1096/17) and by TEVA pharmaceuticals scholarship (SK; PR783187).

Publisher Copyright:
© Kellner et al.

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