Relevance to Autism

Pavinato et al., 2023 reported six individuals with heterozygous RPH3A missense variants: four individuals with intellectual disability and epileptic seizures, and two individuals with autism spectrum disorder and intellectual disability. Additional functional assessment in this report found that both the ID/epilepsy-associated p.Thr450Ser variant and the ASD/ID-associated p.Asn618Ser variant resulted in reduced synaptic localization of GluN2A, increased GluN2A-dependent NMDAR currents, and alteration of postsynaptic calcium levels in neuronal cultures. A de novo loss-of-function variant and multiple de novo missense variants in the RPH3A gene have also been reported in ASD probands (Iossifov et al., 2014; Yuen et al., 2017; Satterstrom et al., 2020; Trost et al., 2022; Wang et al., 2023). Avagliano Trezza et al., 2021 identified RPH3A as a ubiquitination target of UBE3A and demonstrated that an Angelman syndrome-associated missense variant in UBE3A abrogated the interaction with RPH3A.

Molecular Function

The protein encoded by this gene plays an essential role in docking and fusion steps of regulated exocytosis. At the presynaptic level, RPH3A is recruited by RAB3A to the synaptic vesicle membrane in a GTP-dependent manner where it modulates synaptic vesicle trafficking and calcium-triggered neurotransmitter release. In the post-synaptic compartment, RPH3A forms a ternary complex with GRIN2A and DLG4 and regulates NMDA receptor stability.

External Links

References