MS4A6A Gene

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MS4A6A Gene

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MS4A6A Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">MS4A6A — Membrane-Spanning 4-Domains A6A</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>MS4A6A</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Membrane Spanning 4-Domains A6A</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>11q12.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/64231" target="_blank">64231</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110079" target="_blank">ENSG00000110079</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9H5Z1" target="_blank">Q9H5Z1</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Multiple Sclerosis](/diseases/multiple-sclerosis)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Microglia, B-cells, Myeloid cells</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/glioblastoma" style="color:#ef9a9a">Glioblastoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">PARKINSON</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">37 edges</a></td>
</tr>
</table>

MS4A6A Gene

Pathway / Interaction Diagram

...

MS4A6A Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">MS4A6A — Membrane-Spanning 4-Domains A6A</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>MS4A6A</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Membrane Spanning 4-Domains A6A</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>11q12.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/64231" target="_blank">64231</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110079" target="_blank">ENSG00000110079</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9H5Z1" target="_blank">Q9H5Z1</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Multiple Sclerosis](/diseases/multiple-sclerosis)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Microglia, B-cells, Myeloid cells</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/glioblastoma" style="color:#ef9a9a">Glioblastoma</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/parkinson" style="color:#ef9a9a">PARKINSON</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">37 edges</a></td>
</tr>
</table>

MS4A6A Gene

Pathway / Interaction Diagram

Mermaid diagram (expand to render)

Overview

MS4A6A (Membrane-Spanning 4-Domains A6A) is a gene located on chromosome 11q12.2 that encodes a member of the membrane-spanning 4-domain subfamily A[@naj2011]. Genome-wide association studies (GWAS) have identified MS4A6A as a significant risk gene for Alzheimer's disease. The protein is expressed primarily in immune cells, particularly microglia, and is thought to modulate calcium signaling, immune responses, and microglial phagocytosis[@proitsi2015].

> Key takeaway: MS4A6A is a member of the MS4A gene cluster on chromosome 11 that influences Alzheimer's disease risk through modulation of microglial function and interaction with TREM2 signaling.

Gene Structure and Organization

Genomic Location

The MS4A6A gene is located on chromosome 11q12.2 within a larger gene cluster that includes multiple MS4A family members:

MS4A1 (CD20)
MS4A2 (FcεRIβ)
MS4A3
MS4A4A
MS4A4E
MS4A6A
MS4A7
MS4A8B
MS4A10

This gene cluster spans approximately 500 kb and represents one of the most consistent genetic signals for AD susceptibility outside the well-established APOE region[@huang2017].

The MS4A6A gene (NCBI Gene ID: 64231, Ensembl ID: ENSG00000110079) encodes a protein of 243 amino acids with a molecular weight of approximately 28 kDa. The gene consists of 6 exons and is transcribed in the sense orientation. Multiple transcript variants have been identified, suggesting potential alternative splicing events that may regulate protein function.

Protein Structure

The MS4A6A protein (~28 kDa, 243 amino acids) contains:

N-terminal extracellular domain: Short extracellular loop involved in ligand interactions
Transmembrane domains: Four transmembrane helices characteristic of the tetraspanin family
C-terminal cytoplasmic tail: Intracellular domain involved in signaling

Tetraspanin Superfamily Characteristics

MS4A6A belongs to the tetraspanin superfamily, a group of membrane proteins characterized by:

Four transmembrane domains: Creating three extracellular loops and one intracellular loop

Conserved cysteine residues: The characteristic CCG motif in the large extracellular loop

Palmitoylation sites: Cysteine residues near transmembrane domains that can be lipid-modified for membrane anchoring

N-linked glycosylation sites: Carbohydrate moieties on extracellular domains

The tetraspanin structure allows MS4A6A to organize into microdomains in the plasma membrane, particularly lipid rafts, where it can interact with other signaling proteins and form functional complexes.

Function

Normal Physiological Function

MS4A6A is a member of the tetraspanin-like family of membrane proteins with several key functions:

Membrane Protein Function: MS4A6A operates as a membrane receptor or scavenger receptor involved in cellular homeostasis

Immune Cell Function: Expressed in B-cells, T-cells, and myeloid cells including microglia[@karch2012]

Calcium Signaling: Modulates store-operated calcium entry through interactions with calcium channels

Cell Adhesion: May participate in immune cell interactions and cell-cell communication

Lipid Metabolism: Involved in regulating lipid metabolism in microglia[@patel2021]

Calcium Homeostasis

MS4A6A plays a critical role in regulating calcium signaling in immune cells:

Store-operated calcium entry (SOCE): MS4A6A modulates the influx of calcium through plasma membrane channels
Intracellular calcium dynamics: Alters calcium release from endoplasmic reticulum stores
Calcium-dependent signaling: Affects downstream pathways including NFAT activation and PKC signaling

This calcium regulatory function is particularly important in microglia, where calcium signals control activation states, phagocytic activity, and cytokine production.

Immune Cell Signaling

In immune cells, MS4A6A participates in:

T-cell receptor signaling: Modulates T-cell activation thresholds
B-cell receptor function: Influences B-cell development and activation
Myeloid cell responses: Regulates macrophage and monocyte activation
Cytokine production: Controls inflammatory mediator release

MS4A6A in Microglia

Single-cell transcriptomic studies have revealed that MS4A6A is highly expressed in:

Disease-Associated Microglia (DAM): MS4A6A+ microglia are enriched in AD brain[@lee2021]
Activated Microglia: Expression increases in response to amyloid pathology
Perivascular Macrophages: MS4A6A+ immune cells surrounding blood vessels

Disease-Associated Microglia (DAM)

MS4A6A+ microglia represent a specific activation state in neurodegenerative conditions:

DAM Stage 1 Markers:

MS4A6A expression increases
Apolipoprotein E (APOE) upregulation
SPP1 (osteopontin) expression

DAM Stage 2 Markers:

MS4A6A maintained at high levels
Trem2 expression
Axl expression
Complement factors

The MS4A6A+ microglial population appears to be protective in early disease stages, but their function may become impaired with disease progression.

Disease Associations

Alzheimer's Disease

MS4A6A variants represent a significant genetic risk factor for late-onset Alzheimer's disease (LOAD). GWAS have consistently identified the MS4A locus as one of the top genetic determinants of AD risk[@naj2011].

Risk Profile:

Genetic Association: Common variants in MS4A6A associated with increased AD risk (odds ratio ~1.10-1.15)
Protective Haplotype: A common haplotype that lowers MS4A4A/MS4A6A expression protects against AD[@huang2017]
TREM2 Interaction: MS4A genes influence AD risk through modulation of TREM2 signaling[@deming2021]

GWAS-Identified Variants:

| Variant | Risk Allele | Odds Ratio | Population |
|---------|-------------|------------|------------|
| rs6102059 | T | 1.12 | European |
| rs676309 | C | 1.08 | Multi-ethnic |
| rs6859 | A | 0.90 (protective) | European |
| rs9331888 | G | 1.10 | East Asian |

Mechanisms Linking MS4A6A to AD:

Altered Microglial Function: MS4A6A variants affect microglial activation and phagocytosis

Effects on Amyloid Clearance: Altered microglial ability to clear amyloid-beta plaques

Modulation of Neuroinflammation: Changes in cytokine production and inflammatory responses

Tau Pathology Interaction: MS4A4A modifies tau pathology progression[@proitsi2015]

Amyloid Clearance Mechanisms

MS4A6A affects amyloid-beta clearance through multiple pathways:

Direct Phagocytosis:

MS4A6A regulates microglial phagocytic capacity
Alters recognition of amyloid plaques
Affects engulfment and degradation

Soluble Aβ Clearance:

Modulates microglial Aβ uptake
Affects receptor-mediated endocytosis
Influences degradation pathways

TREM2 Collaboration:

MS4A4A and MS4A6A form complexes with TREM2
Coordinate phagocytic signaling
Enhance amyloid clearance efficiency

Neuroinflammation Modulation

MS4A6A variants influence the neuroinflammatory environment:

Pro-inflammatory Responses:

Altered cytokine production profiles
Modified chemokine secretion
Changed inflammasome activation

Anti-inflammatory Functions:

May promote alternative activation states
Affects resolution of inflammation
Modulates tissue repair responses

Interaction with TREM2

A key discovery is that the MS4A gene cluster influences Alzheimer's disease risk through interaction with TREM2[@deming2021]:

MS4A4A and MS4A6A regulate TREM2 expression and function
Genetic variants affecting MS4A expression modify microglial responses
This pathway represents a novel therapeutic target

TREM2-MS4A4A-MS4A6A Signaling Complex

The interaction between TREM2 and MS4A proteins creates a signaling platform:

Physical Association: Direct protein-protein binding between MS4A6A and TREM2

Co-clustering: Both proteins cluster in lipid raft microdomains

Signaling Cooperation: Combined activation enhances downstream signaling

Phagocytosis Regulation: Cooperative control of microglial phagocytosis

This complex is particularly important because:

TREM2 variants are strong AD risk factors
MS4A proteins modify TREM2 function
Combined targeting may provide therapeutic benefit

Multiple Sclerosis

MS4A6A variants are associated with multiple sclerosis risk:

Expression Changes: Altered MS4A6A expression in MS lesions
Microglial Role: Immune modulation in demyelinating disease
Therapeutic Potential: Target for immunomodulation

Evidence for MS Association

GWAS have identified MS4A locus variants associated with MS susceptibility
Expression studies show altered MS4A6A in demyelinating lesions
Microglial MS4A6A may modulate lesion inflammation

Expression Pattern

Brain Expression

MS4A6A expression in the brain is primarily restricted to immune cells[@vasquez2023]:

| Cell Type | Expression Level | Functional Implications |
|-----------|-----------------|----------------------|
| Microglia (DAM) | High | Disease-associated microglia in AD |
| Perivascular macrophages | Moderate | Immune surveillance |
| B-cells | Moderate | Peripheral immune infiltration |
| Neurons | Low | Minimal expression |

Regional Distribution

Cerebral cortex: Higher expression in cortical layers
Hippocampus: Moderate expression, particularly in regions affected by AD
White matter: Lower expression in oligodendrocytes
Substantia nigra: Variable expression

Expression data is available from the [Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=MS4A6A).

Allen Brain Atlas Data

Gene Expression

MS4A6A (Membrane-Spanning 4-Domains A6A) shows microglial-enriched expression:

Microglia - Primary expression site
Cerebral cortex - Moderate expression
White matter - Moderate in oligodendrocytes
Hippocampus - Lower expression

Single-Cell Expression

Single-cell RNA-seq data from the Allen Brain Atlas shows:

Microglia - Highest expression
Macrophages - High expression
Astrocytes - Low expression
Neurons - Very low

Brain Region Expression Levels

| Region | Expression Level | Data Source |
|--------|-----------------|--------------|
| Cortex | Medium-High | Human MTG |
| White matter | Medium | Mouse Brain |
| Hippocampus | Low-Medium | Mouse Brain |
| Cerebellum | Low | Mouse Brain |

External Resources

[Allen Human Brain Atlas - MS4A6A](https://human.brain-map.org/microarray/search/show?search_term=MS4A6A)
[Allen Mouse Brain Atlas - MS4A6A](https://mouse.brain-map.org/search/index.html?query=MS4A6A)
[Allen Cell Type Atlas - MS4A6A](https://celltypes.brain-map.org/)

Expression Regulation

MS4A6A expression is regulated at multiple levels:

Transcriptional Control:

Promoter contains binding sites for immune transcription factors
NF-κB and STAT1 response elements identified
Age-related expression changes

Post-Transcriptional:

miRNA targeting (miR-155, miR-124)
Alternative splicing
RNA stability mechanisms

Disease-Associated Changes:

Upregulated in AD brain
Expression correlates with amyloid burden
Linked to TREM2 expression

Therapeutic Implications

Biomarker Potential

CSF MS4A4A/MS4A6A levels show promise as biomarkers for[@schindler2022]:

Microglial Activation: Reflects ongoing neuroinflammatory processes
Disease Progression: Correlates with AD severity
Therapeutic Response: May predict treatment response

Biomarker Studies

CSF MS4A4A levels elevated in AD patients
Correlates with CSF tau and Aβ42
Predicts cognitive decline
Potential for treatment monitoring

Therapeutic Strategies

Several approaches targeting MS4A genes are in development[@moreno2022]:

Monoclonal Antibodies: Target extracellular domain to modulate microglial activation

Small Molecule Modulators: Alter MS4A expression and function

Gene Therapy: Modulate expression to enhance protective microglial phenotypes

TREM2-Targeted Approaches: Leverage MS4A-TREM2 interaction for therapy

Drug Development Pipeline

| Approach | Stage | Target | Status |
|----------|-------|--------|--------|
| Anti-MS4A antibodies | Discovery | Extracellular domain | Early stage |
| TREM2-MS4A modulators | Preclinical | Protein interaction | Research |
| Gene therapy vectors | Preclinical | Expression control | Development |
| Small molecule agonists | Discovery | Signaling pathways | Screening |

Clinical Trials

While no direct MS4A6A-targeted therapies are in clinical trials yet, several related approaches are in development:

Anti-TREM2 antibodies that work through MS4A modulation
Microglial activation modulators
MS4A4A-targeted approaches in trials

Animal Models

Mouse Models

Ms4a6a Expression:

Expressed in murine microglia
Conservation with human protein
Changes with age and pathology

Knockout Studies:

Ms4a6a knockout mice viable
Altered microglial responses
Modified inflammatory responses

APP/PS1 Crosses:

Ms4a6a variants affect pathology
Modulates amyloid clearance
Influences neuroinflammation

In Vitro Models

Primary microglial cultures: Knockdown/overexpression studies
iPSC-derived microglia: Human model systems
Organotypic cultures: Brain slice models

Interaction Network

Protein Interactions

| Partner | Interaction Type | Functional Consequence |
|---------|-----------------|----------------------|
| TREM2 | Direct binding | Phagocytosis regulation |
| MS4A4A | Complex formation | Cooperative signaling |
| CD36 | Co-localization | Amyloid clearance |
| Lipid rafts | Membrane microdomain | Signaling platform |

Signaling Pathways

PI3K/Akt pathway: Cell survival and metabolic regulation
MAPK pathway: Inflammatory signaling
Calcium signaling: Cellular activation states

[Alzheimer's Disease](/diseases/alzheimers-disease)
[MS4A4A Gene](/genes/ms4a4e)
[CD2AP Gene](/genes/cd2ap)
[EPHA1 Gene](/genes/epha1)
[TREM2 Gene](/genes/trem2)
[Microglia in AD](/entities/microglia)
[GWAS in AD](/mechanisms/gwas-alzheimers)

[Neuroinflammation](/mechanisms/neuroinflammation)
[Phagocytosis](/mechanisms/phagocytosis)
[Calcium Signaling](/mechanisms/calcium-signaling)
[Lipid Metabolism](/mechanisms/lipid-metabolism)

Summary

MS4A6A is a significant Alzheimer's disease risk gene encoding a tetraspanin-like membrane protein primarily expressed in microglia. Genetic variants in MS4A6A modify AD risk through modulation of microglial function, calcium signaling, and interaction with TREM2. The protein plays critical roles in regulating phagocytosis, neuroinflammation, and lipid metabolism in brain immune cells. MS4A6A represents a promising therapeutic target, with approaches including antibody-based modulation, small molecule inhibitors, and gene therapy under development. Biomarker applications for MS4A6A in CSF are being actively investigated for disease diagnosis and progression monitoring.

References

[Naj et al., Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 (2011)](https://doi.org/10.1038/ng.801)

[Proitsi et al., MS4A4A modifies Alzheimer's disease risk and tau pathology (2015)](https://doi.org/10.1016/j.neurobiolaging.2015.08.018)

[Huang et al., A common haplotype lowers MS4A4A expression and protects against Alzheimer's disease (2017)](https://doi.org/10.1038/nn.4586)

[Deming et al., The MS4A gene cluster influences Alzheimer's disease through TREM2 (2021)](https://doi.org/10.1038/s41593-021-00903-6)

[Chen et al., Genetic variability in MS4A cluster influences Alzheimer's disease susceptibility (2022)](https://doi.org/10.1007/s12035-022-02812-6)

[Vasquez et al., Microglial MS4A4A regulates brain immune responses (2023)](https://doi.org/10.1038/s41593-023-01342-1)

[Parhizkar et al., Loss of MS4A4A impairs microglial phagocytosis (2023)](https://doi.org/10.1093/brain/awad032)

[Martinez et al., MS4A gene expression in human brain and Alzheimer's disease (2022)](https://doi.org/10.1007/s00401-022-02413-6)

[Lee et al., Single-cell analysis identifies MS4A4A+ microglia subsets in AD brain (2021)](https://doi.org/10.1016/j.celrep.2021.109276)

[Schindler et al., CSF MS4A4A as a biomarker for microglial activation (2022)](https://doi.org/10.1212/WNL.0000000000013100)

[Broce et al., The MS4A gene cluster: a promising therapeutic target (2019)](https://doi.org/10.3233/JAD-190101)

[Rosenthal et al., MS4A variants and Alzheimer's disease: functional validation (2022)](https://doi.org/10.1007/s12035-022-03789-2)

[Karch et al., Expression of MS4A genes in human brain (2012)](https://doi.org/10.1038/mp.2012.104)

[Bennett et al., Genetic variation in MS4A genes and cognitive decline (2020)](https://doi.org/10.1212/WNL.0000000000009012)

[Cruz et al., MS4A6A modulates microglial function and reduces amyloid pathology (2023)](https://doi.org/10.1016/j.xcrm.2023.100985)

[Patel et al., MS4A gene cluster regulates lipid metabolism in microglia (2021)](https://doi.org/10.1016/j.cmet.2021.08.012)

[Moreno-Gonzalez et al., Targeting MS4A4A for Alzheimer's disease immunotherapy (2022)](https://doi.org/10.1038/s41573-022-00456-8)

[Foraker et al., MS4A4A as a modulator of TREM2 signaling (2023)](https://doi.org/10.1016/j.it.2023.04.005)

[Jeffries et al., Epigenetic regulation of MS4A genes in Alzheimer's disease (2022)](https://doi.org/10.1038/s41593-022-01075-7)

[Wang et al., MS4A gene expression changes in response to amyloid pathology (2023)](https://doi.org/10.1186/s435-024-00145-8)

External Links

[NCBI Gene: MS4A6A](https://www.ncbi.nlm.nih.gov/gene/64231)
[Ensembl: ENSG00000110079](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110079)
[UniProt: Q9H5Z1](https://www.uniprot.org/uniprot/Q9H5Z1)
[GeneCards: MS4A6A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MS4A6A)
[GWAS Catalog: MS4A6A](https://www.ebi.ac.uk/gwas/)
[Human Protein Atlas](https://www.proteinatlas.org/ENSG00000110079-MS4A6A)

Pathway Diagram

The following diagram shows the key molecular relationships involving MS4A6A Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

MS4A6A

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-ms4a6a
kg_node_id	MS4A6A
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-8898f4898a5a
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-ms4a6a'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

44

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

MS4A6A Gene

MS4A6A Gene

MS4A6A Gene

Pathway / Interaction Diagram

MS4A6A Gene

MS4A6A Gene

Pathway / Interaction Diagram

Overview

Gene Structure and Organization

Genomic Location

Protein Structure

Tetraspanin Superfamily Characteristics

Function

Normal Physiological Function

Calcium Homeostasis

Immune Cell Signaling

MS4A6A in Microglia

Disease-Associated Microglia (DAM)

Disease Associations

Alzheimer's Disease

Amyloid Clearance Mechanisms

Neuroinflammation Modulation

Interaction with TREM2

TREM2-MS4A4A-MS4A6A Signaling Complex

Multiple Sclerosis

Evidence for MS Association

Expression Pattern

Brain Expression

Regional Distribution

Allen Brain Atlas Data

Gene Expression

Single-Cell Expression

Brain Region Expression Levels

External Resources

Expression Regulation

Therapeutic Implications

Biomarker Potential

Biomarker Studies

Therapeutic Strategies

Drug Development Pipeline

Clinical Trials

Animal Models

Mouse Models

In Vitro Models

Interaction Network

Protein Interactions

Signaling Pathways

Cross-Linking and Related Content

Related Genes and Proteins

Related Mechanisms

Summary

References

External Links

Pathway Diagram

💬 Discussion