Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically...

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• RPH3A protein stabilizes GluN2A subunits of NMDA receptors, crucial for synaptic plasticity and cognition.
• Dysregulation of NMDA receptors is implicated in various neurodevelopmental disorders.

Purpose of the Study:

• To investigate the impact of RPH3A variants in individuals with neurodevelopmental disorders.
• To characterize the functional consequences of identified RPH3A variants using in silico and in vitro models.

Main Methods:

• Trio-based exome sequencing and large-scale genetic data screening identified RPH3A variants.
• In vitro studies utilized rat hippocampal neuronal cultures to assess variant effects.
• Electrophysiological recordings and dendritic spine morphology analysis were performed.

Main Results:

• Six heterozygous RPH3A variants were identified in patients with neurodevelopmental disorders, including epilepsy and autism spectrum disorder.
• Specific variants (p.Thr450Ser, p.Asn618Ser) altered GluN2A localization and increased NMDA receptor currents.
• RPH3A variants affected postsynaptic calcium levels and dendritic spine morphology.

Conclusions:

• Missense gain-of-function variants in RPH3A disrupt synaptic function by increasing extrasynaptic NMDA receptors.
• These disruptions lead to a spectrum of neurodevelopmental conditions, from epilepsy to autism.
• RPH3A variants represent a novel genetic cause for diverse neurodevelopmental phenotypes.