Gene and Protein: The RPH3A gene encodes Rabphilin 3A, a synaptic protein that interacts with the GluN2A subunit of the NMDA receptor and the scaffolding protein PSD-95 to stabilize the receptor complex at the postsynaptic density. It also has presynaptic functions related to vesicle trafficking and glutamate release.
Variants: Currently, the disorder has been associated with heterozygous missense variants, including p.(Gln73His), p.(Arg209Lys), p.(Arg235Ser), p.(Thr450Ser), p.(Gln508His), and p.(Asn618Ser).
Pathophysiologic Mechanism: The pathogenic mechanism is complex, involving both pre- and post-synaptic dysfunction. Variants appear to act through a gain-of-function mechanism, increasing GluN2A-containing NMDA receptor currents and promoting their localization to extrasynaptic sites. This leads to altered synaptic function and aberrant postsynaptic calcium signaling. Concurrently, variants can cause a reduction in presynaptic glutamate release and impair the normal synaptic retention of GluN2A receptors, suggesting a partial loss-of-function in specific activities.
Diagnostic Testing: Diagnosis is established by the identification of a heterozygous pathogenic variant in RPH3A through molecular genetic testing such as exome or genome sequencing.
RPH3A