DLG4 Gene (PSD-95): Function, Mutations, and Associated Diseases | NCBI, UniProt, OMIM

The DLG4 gene encodes postsynaptic density protein 95 (PSD-95), a member of the membrane-associated guanylate kinase (MAGUK) family. PSD-95 is a critical scaffolding protein localized at excitatory glutamatergic synapses, where it organizes neurotransmitter receptors (e.g., NMDA and AMPA receptors), ion channels, and signaling molecules. It plays a central role in synaptic maturation, plasticity, and learning. De novo loss-of-function mutations in DLG4 are associated with a neurodevelopmental disorder characterized by intellectual disability, developmental delay, and behavioral abnormalities. The protein contains three PDZ domains, an SH3 domain, and a guanylate kinase (GK) domain, which mediate its interactions with a wide array of synaptic proteins.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Glutamatergic synapse (KEGG: hsa04724)

• Long-term potentiation (KEGG: hsa04720)

• Long-term depression (KEGG: hsa04730)

• Neuroactive ligand-receptor interaction (KEGG: hsa04080)

• Postsynaptic density protein signaling (Reactome: R-HSA-6794362)

PSD-95 is a 724-amino acid protein with a molecular weight of approximately 80 kDa. It contains three N-terminal PDZ domains (PDZ1-3), an SH3 domain, and a C-terminal guanylate kinase (GK) domain. PDZ1 and PDZ2 bind to the C-termini of NMDA receptor subunits (GluN2A/B) and potassium channels (Kv1.4). PDZ3 interacts with AMPA receptor auxiliary subunits (e.g., stargazin/TARPs). The SH3-GK domain forms an intramolecular interaction that regulates protein conformation. PSD-95 is palmitoylated at N-terminal cysteines (Cys3, Cys5), which is essential for its synaptic targeting and clustering. It is a core organizer of the postsynaptic density, linking receptors to the actin cytoskeleton and downstream signaling pathways (e.g., Ras/ERK, PI3K/Akt).