protein
Disks large homolog 4
Gene
DLG4
Organism
Homo sapiens(9606)
Length
724 aa
Mass
80,495 Da
DLG4 (disks large homolog 4) is a postsynaptic scaffolding protein encoded by 724 amino acids that plays a critical role in synaptogenesis and synaptic plasticity (UniProt: P78352). It functions as a structural platform for clustering synaptic proteins, particularly interacting with the cytoplasmic tail of NMDA receptor subunits and potassium channels. DLG4 is required for synaptic plasticity associated with NMDA receptor signaling and regulates AMPA-type glutamate receptor immobilization at the postsynaptic density.
DLG4 is expressed in hippocampal neurons and other neural tissues where it influences the balance of excitatory to inhibitory synapses. The protein cooperates with FYN to stabilize palmitoyltransferase ZDHHC5 at synaptic membranes through phosphorylation-dependent mechanisms. DLG4 is associated with intellectual developmental disorder, autosomal dominant 62 (MRD62), a condition characterized by mild to moderately impaired intellectual development.
DLG4 carries SFARI classifications for syndromic autism (SFARI Cat S), indicating curated evidence linking this gene to autism spectrum disorder within syndromic presentations. Its role in fundamental synaptic plasticity and postsynaptic organization positions it as relevant to neurodevelopmental dysfunction.
Generated from the curated entity record below. May contain errors — verify against source links.
Proteomics Evidence · AD
↓ Down in ADP3
not detected
P2
not detected
S2
-1.816
S3
not detected
Mean log₂FC across detected fractions: -1.816 (1 of 4 fractions detected)
Human post-mortem AD brain vs age-matched controls, TMT-labeled, 4 subcellular fractions (P2, P3, S2, S3), DDA proteomics.
Genetic Evidence · ASD
Source: SFARI Gene database · gene.sfari.org
This protein is implicated in both ASD and Alzheimer's Disease. View all cross-disease proteins →
Related Publications
Browse all →Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.
Dujardin Simon et al.Nature medicine2020PMID 32572268Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression.
Bai Bing et al.Neuron2020PMID 31926610A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease.
Seyfried Nicholas T et al.Cell systems2017PMID 27989508Large-scale deep multi-layer analysis of Alzheimer's disease brain reveals strong proteomic disease-related changes not observed at the RNA level.
Johnson Erik C B et al.Nature neuroscience2022PMID 35115731Organization and regulation of gene transcription.
Cramer PatrickNature2019PMID 31462772Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
Ruzzo Elizabeth K et al.Cell2019PMID 31398340Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.
Guo Hui et al.Molecular autism2018PMID 30564305Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
C Yuen Ryan K et al.Nature neuroscience2017PMID 28263302Identification of common genetic risk variants for autism spectrum disorder.
Grove Jakob et al.Nature genetics2019PMID 30804558Synaptic, transcriptional and chromatin genes disrupted in autism.
De Rubeis Silvia et al.Nature2014PMID 25363760
Function
Postsynaptic scaffolding protein that plays a critical role in synaptogenesis and synaptic plasticity by providing a platform for the postsynaptic clustering of crucial synaptic proteins. Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B. Also regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression (By similarity). Under basal conditions, cooperates with FYN to stabilize palmitoyltransferase ZDHHC5 at the synaptic membrane through FYN-mediated phosphorylation of ZDHHC5 and its subsequent inhibition of association with endocytic proteins (PubMed:26334723)
Disease associations
Intellectual developmental disorder, autosomal dominant 62MRD62
An autosomal dominant form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD62 is characterized by mild to moderately impaired intellectual development.
Sources
Last updated 5/8/2026, 1:05:23 AM