Pavinato, Lisa;
Stanic, Jennifer;
Barzasi, Marta;
Gurgone, Antonia;
Chiantia, Giuseppe;
Cipriani, Valentina;
Eberini, Ivano;
... Brusco, Alfredo; + view all
(2023)
Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder.
Genetics in Medicine
, 25
(11)
, Article 100922. 10.1016/j.gim.2023.100922.
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Abstract
PURPOSE: RPH3A encodes a protein involved in the stabilization of GluN2A subunit of NMDA-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition. We investigated the effect of variants in RPH3A in patients with neurodevelopmental disorders (NDDs). // METHODS: By using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified six heterozygous variants in RPH3A. In silico and in vitro models, including rat hippocampal neuronal cultures, have been used to characterize the effect of the variants.// RESULTS: Four cases had a NDD with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and two cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder (ASD). Using neuronal cultures, we demonstrated that p.(Thr450Ser) and p.(Asn618Ser) reduce the synaptic localization of GluN2A; p.(Thr450Ser) also increased the surface levels of GluN2A. Electrophysiological recordings showed increased GluN2A-dependent NMDAR currents for both variants, and alteration of postsynaptic calcium levels. Finally, expression of the Rph3AThr450Ser variant in neurons affected dendritic spine morphology. // CONCLUSION: Overall, we provide evidence that missense gain of function variants in RPH3A increase GluN2A-containing NMDARs at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to ASD.
| Type: | Article |
|---|---|
| Title: | Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.gim.2023.100922 |
| Publisher version: | https://doi.org/10.1016/j.gim.2023.100922 |
| Language: | English |
| Additional information: | 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/4.0/ |
| Keywords: | RPH3A, epilepsy, excitatory synapse, neurodevelopmental disorder, rabphilin |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10173344 |
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