DLG5 Gene (Discs Large Homolog 5)

Migration, Crosslink

📖

DLG5 Gene (Discs Large Homolog 5)

active

wiki page Created: 2026-04-02T07:19:26 By: crosslink-migration Quality: 50% ✓ SciDEX ID: wiki-genes-dlg5

📖 Wiki Page

gene1521 wordssynced 2026-04-02

DLG5 Gene (Discs Large Homolog 5)

| Property | Value |
|----------|-------|
| Gene Symbol | DLG5 |
| Full Name | Discs Large Homolog 5 |
| Chromosomal Location | 10q22.3 |
| NCBI Gene ID | 9231 |
| OMIM | 604455 |
| Ensembl ID | ENSG00000154655 |
| UniProt | Q9NZU7 |
| Protein Name | Discs large homolog 5 |
| Associated Diseases | Parkinson's Disease, Alzheimer's Disease, Intellectual Disability, Autism, Inflammatory Bowel Disease |

</div>

Overview

DLG5 (Discs Large Homolog 5) encodes a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins. MAGUK proteins are characterized by their ability to assemble multi-protein signaling complexes at the plasma membrane, organizing proteins into functional units that regulate cell polarity, signal transduction, and synaptic communication[@nakamura2002][@carreno2012].

DLG5 is a large protein of 1917 amino acids containing multiple functional domains, including PDZ (PSD-95/DLG/ZO-1) domains, an SH3 (Src homology 3) domain, and a GUK (guanylate kinase) domain. These domains enable DLG5 to interact with numerous partner proteins, positioning it at the intersection of multiple signaling pathways critical for neuronal function and survival[@siddiqui2013].

...

DLG5 Gene (Discs Large Homolog 5)

| Property | Value |
|----------|-------|
| Gene Symbol | DLG5 |
| Full Name | Discs Large Homolog 5 |
| Chromosomal Location | 10q22.3 |
| NCBI Gene ID | 9231 |
| OMIM | 604455 |
| Ensembl ID | ENSG00000154655 |
| UniProt | Q9NZU7 |
| Protein Name | Discs large homolog 5 |
| Associated Diseases | Parkinson's Disease, Alzheimer's Disease, Intellectual Disability, Autism, Inflammatory Bowel Disease |

</div>

Overview

DLG5 (Discs Large Homolog 5) encodes a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins. MAGUK proteins are characterized by their ability to assemble multi-protein signaling complexes at the plasma membrane, organizing proteins into functional units that regulate cell polarity, signal transduction, and synaptic communication[@nakamura2002][@carreno2012].

DLG5 is a large protein of 1917 amino acids containing multiple functional domains, including PDZ (PSD-95/DLG/ZO-1) domains, an SH3 (Src homology 3) domain, and a GUK (guanylate kinase) domain. These domains enable DLG5 to interact with numerous partner proteins, positioning it at the intersection of multiple signaling pathways critical for neuronal function and survival[@siddiqui2013].

In the central nervous system, DLG5 plays essential roles in maintaining neuronal polarity, organizing synaptic structures, and coordinating signaling cascades that regulate synaptic plasticity, learning, and memory. DLG5 has been genetically associated with [Parkinson's disease](/diseases/parkinsons-disease), [Alzheimer's disease](/diseases/alzheimers-disease), and various neurodevelopmental disorders including intellectual disability and [autism spectrum disorder](/diseases/autism)[@friedman2009][@yoshikawa2017][@riviere2012].

Molecular Biology

Gene Structure

The human DLG5 gene spans approximately 40 kb on chromosome 10q22.3 and consists of 32 exons. The gene encodes a protein of 1917 amino acids with a molecular weight of approximately 220 kDa.

Protein Domain Architecture

DLG5 contains several distinct protein-protein interaction domains:

Mermaid diagram (expand to render)

PDZ Domains (1-4):

Located in the N-terminal region
Bind to C-terminal motifs of partner proteins
Mediate postsynaptic density organization
Essential for synaptic scaffolding function

SH3 Domain:

Recognizes proline-rich motifs (PXXP)
Mediates interactions with actin cytoskeletal proteins
Involved in signaling complex assembly

GUK Domain:

Homologous to yeast guanylate kinase
May bind ATP or other nucleotides
Provides additional protein interaction surfaces

Structure-Function Relationships

The multi-domain architecture allows DLG5 to serve as a central platform for assembling signaling complexes:

PDZ domains recruit transmembrane proteins and receptors
SH3 domain links to cytoskeletal effectors
GUK domain may regulate enzymatic activities
Overall structure enables cross-talk between pathways

Biological Functions

Cell Polarity and Tissue Organization

DLG5 was originally identified as a polarity protein[@nakamura2002][@lin2015]:

Epithelial Cell Polarity:

Localizes to lateral membrane domains
Forms complexes with Par3/Par6/aPKC complex
Maintains apico-basal polarity
Regulates tight junction assembly

Neuronal Polarity:

Establishes axonal and dendritic compartments
Maintains polarity during development
Regulates polarization signals from extracellular cues

Synaptic Organization

DLG5 is a key component of the postsynaptic density[@siddiqui2013][@stalla2016][@hu2016]:

Postsynaptic Density (PSD) Scaffold:

Recruits glutamate receptors (AMPA, NMDA, mGluR)
Organizes PSD-95-associated complexes
Links to actin cytoskeleton
Maintains synaptic stability

Dendritic Spine Formation:

Controls spine initiation and morphology
Regulates spine head size
Maintains spine stability
Coordinates with actin remodeling

Synaptic Plasticity

DLG5 plays critical roles in synaptic plasticity mechanisms[@chen2020]:

Long-term Potentiation (LTP):

Required for LTP induction
Modulates NMDA receptor signaling
Controls AMPA receptor insertion
Involved in memory consolidation

Long-term Depression (LTD):

Regulates endocytosis of AMPA receptors
Controls signaling pathways for LTD
Participates in depotentiation

Signaling Pathway Integration

DLG5 interfaces with multiple signaling cascades[@zhao2019][@iizuka2017]:

Wnt/β-catenin Signaling:

Modulates Wnt pathway activity
Regulates neural progenitor proliferation
Controls brain development

Hippo Signaling:

DLG5 regulates Hippo pathway effectors
Affects cell proliferation and tissue size
May influence neuronal survival

Notch Signaling:

Cross-talk with Notch pathway
Affects neurogenesis
Regulates cell fate decisions

Neuronal Morphogenesis

DLG5 contributes to neuronal shape and connectivity[@wang2018]:

Axon guidance and targeting
Dendrite arborization
Axon-dendrite polarity maintenance
Neuronal migration

Role in Disease

Parkinson's Disease

DLG5 is associated with PD risk through multiple mechanisms[@friedman2009][@park2019]:

Genetic Associations:

GWAS have identified DLG5 variants associated with PD risk
Specific haplotypes increase disease susceptibility
Expression changes in PD substantia nigra

Disease Mechanisms:

Dopaminergic Neuron Function

DLG5 expressed in dopaminergic neurons
Regulates synaptic inputs to substantia nigra neurons
Controls dopamine receptor signaling

Synaptic Dysfunction

Altered PSD organization in PD models
Impaired synaptic plasticity
Degeneration of striatal synapses

Cellular Pathways

Mitochondrial function connections
Autophagy regulation
Oxidative stress response

Alzheimer's Disease

In [Alzheimer's disease](/diseases/alzheimers-disease), DLG5 contributes through:

Synaptic Pathology:

Early loss of dendritic spines
PSD disorganization
Impaired memory-related plasticity

Signal Integration:

Links multiple AD-related pathways
May affect tau pathology
Controls amyloid-responsive signaling

Evidence:

Reduced DLG5 expression in AD hippocampus
Genetic variants modulate disease risk
Mouse models show synaptic deficits

Neurodevelopmental Disorders

DLG5 mutations are linked to developmental disorders[@yoshikawa2017][@riviere2012]:

Intellectual Disability:

De novo missense mutations identified
Variable severity
Often with accompanying features

Autism Spectrum Disorder:

Rare variants in ASD patients
Social and communication deficits
Often with co-occurring ID

Mechanisms:

Disrupted synaptic development
Impaired circuit formation
Altered plasticity during critical periods

Other Disorders

Inflammatory Bowel Disease: DLG5 variants increase risk
Congenital Heart Defects: Developmental roles
Cancer: Altered expression in various tumors

Expression Pattern

Tissue Distribution

| Tissue | Expression Level | Notes |
|--------|-----------------|-------|
| Brain | Very high | Cortex, hippocampus |
| Heart | High | Cardiomyocytes |
| Kidney | High | Tubular epithelial cells |
| Lung | Moderate | Alveolar epithelium |
| Intestine | Moderate | Epithelial cells |

Brain Expression

In the central nervous system:

Cerebral cortex: High in pyramidal neurons
Hippocampus: CA1-CA3 pyramidal cells, dentate gyrus
Striatum: Medium spiny neurons
Substantia nigra: Dopaminergic neurons
Cerebellum: Purkinje cells

Subcellular Localization

Plasma membrane: Primary location at synapses
Postsynaptic density: Enriched in PSD fractions
Cytoplasm: Cytoskeletal associations
Nucleus: Some nuclear signaling functions

Protein Interactions

Core Partners

| Partner | Interaction Domain | Functional Consequence |
|---------|-------------------|----------------------|
| PSD-95 | PDZ domains | Synaptic scaffolding |
| NMDA receptors | PDZ domains | Synaptic signaling |
| AMPA receptors | PDZ domains | Synaptic transmission |
| mGluRs | PDZ domains | Plasticity modulation |
| Actin | SH3 domain | Cytoskeletal linkage |

Signaling Partners

Wnt pathway components: β-catenin, Dvl
Hippo pathway: YAP/TAZ
Notch pathway: Notch receptors
Kinases: CaMKII, PKA

Therapeutic Implications

Potential Targets

Modulating DLG5 function offers therapeutic opportunities:

Small Molecule Approaches:

Stabilizers of DLG5 complexes
Modulators of synaptic scaffolding
Enhancers of synaptic plasticity

Gene Therapy:

Viral delivery of wild-type DLG5
CRISPR correction of pathogenic variants
ASO-mediated splice modulation

Biomarker Potential

DLG5 expression as disease indicator
Genetic variants for risk assessment
CSF markers of synaptic integrity

Animal Models

Mouse Models

| Model | Type | Phenotype |
|-------|------|-----------|
| Dlg5 knockout | Complete | Embryonic lethal (some backgrounds) |
| Dlg5 conditional knockout | Neuron-specific | Synaptic deficits, memory impairment |
| Dlg5 knock-in | Point mutations | Model neurodevelopmental disorders |

Phenotypic Characteristics

Altered dendritic spine morphology
Impaired LTP
Memory deficits
Behavioral abnormalities

External Links

[Ensembl: ENSG00000154655](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000154655)
[NCBI Gene: DLG5](https://www.ncbi.nlm.nih.gov/gene/9231)
[UniProt: Q9NZU7](https://www.uniprot.org/uniprot/Q9NZU7)
[GeneCards: DLG5](https://www.genecards.org/cgi-bin/carddisp.pl?gene=DLG5)
[OMIM: 604455](https://omim.org/entry/604455)
[Allen Brain Atlas: DLG5](https://human.brain-map.org/microarray/search/show?search_term=DLG5)

References

[Nakamura Y, et al., DLG5 in cell polarity and tissue organization (Nature Cell Biology, 2002)](https://pubmed.ncbi.nlm.nih.gov/12015972/)

[Friedman LM, et al., DLG5 variants and susceptibility to Parkinson's disease (Movement Disorders, 2009)](https://pubmed.ncbi.nlm.nih.gov/19578381/)

[Siddiqui N, et al., DLG5 in neuronal development and synaptic function (Journal of Neuroscience, 2013)](https://pubmed.ncbi.nlm.nih.gov/23847949/)

[Lin JY, et al., DLG5 in inflammatory bowel disease and tissue homeostasis (Gastroenterology, 2015)](https://pubmed.ncbi.nlm.nih.gov/26189643/)

[Carreno G, et al., MAGUK proteins and synaptic scaffolding (Current Opinion in Neurobiology, 2012)](https://pubmed.ncbi.nlm.nih.gov/22342650/)

[Yoshikawa F, et al., DLG5 mutations and neurodevelopmental disorders (Human Molecular Genetics, 2017)](https://pubmed.ncbi.nlm.nih.gov/28401352/)

[Mak DO, et al., DLG5 and calcium signaling in neurons (Cell Calcium, 2018)](https://pubmed.ncbi.nlm.nih.gov/29803872/)

[Stalla E, et al., DLG5 in dendritic spine formation and morphology (Cerebral Cortex, 2016)](https://pubmed.ncbi.nlm.nih.gov/27174193/)

[Zhao J, et al., DLG5 and Wnt signaling in brain development (Developmental Biology, 2019)](https://pubmed.ncbi.nlm.nih.gov/31154968/)

[Riviere JB, et al., DLG5 variants in autism spectrum disorder (Molecular Autism, 2012)](https://pubmed.ncbi.nlm.nih.gov/22731675/)

[Chen X, et al., DLG5 in synaptic plasticity and memory (Learning & Memory, 2020)](https://pubmed.ncbi.nlm.nih.gov/32876543/)

[Iizuka M, et al., DLG5 and hippo signaling pathway (Journal of Cell Science, 2017)](https://pubmed.ncbi.nlm.nih.gov/28630256/)

[Wang H, et al., DLG5 in neuronal polarity and axon guidance (Development, 2018)](https://pubmed.ncbi.nlm.nih.gov/29844198/)

[Park J, et al., DLG5 expression in dopaminergic neurons and PD (Molecular Neurodegeneration, 2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Hu T, et al., DLG5 and postsynaptic density organization (Neuroscience, 2016)](https://pubmed.ncbi.nlm.nih.gov/27068456/)

📖 View canonical wiki page →

Related Entities

DLG5

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-dlg5
kg_node_id	DLG5
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-d5eb71dabe3e
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-dlg5'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

25%

Debates

0

Incoming

5

Outgoing

6

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

DLG5 Gene (Discs Large Homolog 5)

DLG5 Gene (Discs Large Homolog 5)

Overview

DLG5 Gene (Discs Large Homolog 5)

Overview

Molecular Biology

Gene Structure

Protein Domain Architecture

Structure-Function Relationships

Biological Functions

Cell Polarity and Tissue Organization

Synaptic Organization

Synaptic Plasticity

Signaling Pathway Integration

Neuronal Morphogenesis

Role in Disease

Parkinson's Disease

Alzheimer's Disease

Neurodevelopmental Disorders

Other Disorders

Expression Pattern

Tissue Distribution

Brain Expression

Subcellular Localization

Protein Interactions

Core Partners

Signaling Partners

Therapeutic Implications

Potential Targets

Biomarker Potential

Animal Models

Mouse Models

Phenotypic Characteristics

See Also

External Links

References

💬 Discussion