Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder

Authors

Lisa Pavinato, University of Turin, Italy
Jennifer Stanic, University of the Studies of Milan, Italy
Marta Barzasi, University of the Studies of Milan, Italy
Antonia Gurgone, University of Turin, Italy
Giuseppe Chiantia, University of Turin, Italy
Valentina Cipriani, Queen Mary University of London, United Kingdom
Ivano Eberini, University of the Studies of Milan, Italy
Luca Palazzolo, University of the Studies of Milan, Italy
Monica Di Luca, University of the Studies of Milan, Italy
Prem Chand, Aga Khan UniversityFollow

Document Type

Article

Department

Paediatrics and Child Health

Abstract

Purpose: RPH3A encodes a protein involved in the stabilization of GluN2A subunit of N-methyl-D-aspartate (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.
Methods: By using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified 6 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 neurodevelopmental disorder with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and 2 cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder. 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 NMDA ionotropic glutamate receptor 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 NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to autism spectrum disorder.

Comments

Pagination are not provided by the author/publisher.

Publication (Name of Journal)

Genetics in Medicine

Recommended Citation

Pavinato, L., Stanic, J., Barzasi, M., Gurgone, A., Chiantia, G., Cipriani, V., Eberini, I., Palazzolo, L., Luca, M. D., Chand, P. (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).
Available at: https://ecommons.aku.edu/pakistan_fhs_mc_women_childhealth_paediatr/1399