DLG3

DLG3, also known as SAP102, is a member of the Discs large homolog (DLG) family within the membrane-associated guanylate kinases (MAGUKs). The DLG3 gene encodes a scaffolding protein that localizes to the postsynaptic density of glutamatergic synapses in the brain, where it coordinates signaling by linking neurotransmitter receptors, channels, and cytoskeletal elements.

Structure and expression: SAP102 contains PDZ, SH3, and guanylate kinase-like domains typical of MAGUK proteins. It interacts with NMDA receptor subunits and other postsynaptic partners. Expression of SAP102 is relatively high during early brain development and at developing synapses, and it declines in mature circuits as PSD-95 and related scaffolds become more dominant.

Function: As a scaffolding protein, SAP102 organizes signaling complexes that regulate receptor trafficking, synapse assembly, and synaptic plasticity. Through its PDZ-mediated interactions, it modulates NMDA receptor function and contributes to synaptic maturation and strengthening processes important for learning and memory.

Clinical significance: Pathogenic variants in DLG3 have been associated with X-linked neurodevelopmental disorders, including intellectual disability and autism spectrum disorders. Experimental models indicate that loss or disruption of DLG3 impairs NMDA receptor signaling and synaptic plasticity, producing deficits in learning- and memory-related behaviors in animals. The phenotypic spectrum in humans remains variable, reflecting the broader impact of synaptic scaffolding on neurodevelopment.