MS4A6E Gene

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gene2054 wordssynced 2026-04-02

MS4A6E — Membrane Spanning 4-Domains A6E

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">MS4A6E</th></tr>
<tr><td><b>Full Name</b></td><td>Membrane Spanning 4-Domains A6E</td></tr>
<tr><td><b>Gene Symbol</b></td><td>MS4A6E</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>11q12.2</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td><a href="https://www.ncbi.nlm.nih.gov/gene/9315" target="_blank">9315</a></td></tr>
<tr><td><b>OMIM</b></td><td><a href="https://omim.org/entry/606546" target="_blank">606546</a></td></tr>
<tr><td><b>Ensembl ID</b></td><td>ENSG00000110079</td></tr>
<tr><td><b>UniProt ID</b></td><td><a href="https://www.uniprot.org/uniprot/Q9H3Y5" target="_blank">Q9H3Y5</a></td></tr>
<tr><td><b>Protein Length</b></td><td>253 amino acids</td></tr>
<tr><td><b>Category</b></td><td>Immune/Microglial/AD Risk Gene</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

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MS4A6E — Membrane Spanning 4-Domains A6E

Overview

Mermaid diagram (expand to render)

MS4A6E (Membrane Spanning 4-Domains A6E) is a member of the MS4A gene family located on chromosome 11q12.2. This gene has emerged as a significant genetic risk factor for [Alzheimer's Disease](/diseases/alzheimers-disease) through genome-wide association studies (GWAS), with the MS4A gene cluster on chromosome 11 representing one of the most important AD risk loci identified in recent years. MS4A6E is expressed primarily in [microglia](/cell-types/microglia), the resident immune cells of the brain, where it plays critical roles in phagocytosis, lipid metabolism, and immune surveillance.

The MS4A gene family comprises at least 13 genes clustered on chromosome 11q12, all encoding transmembrane proteins with characteristic multiple hydrophobic membrane-spanning domains. While MS4A1 (CD20) has been extensively studied as a therapeutic target in B-cell lymphomas, the neurological functions of MS4A4A, MS4A6E, and related family members have only recently come into focus through genetic studies of neurodegenerative diseases.

Gene Family Context

MS4A Gene Cluster Architecture

The MS4A gene family is organized as a tight cluster on chromosome 11q12.2, spanning approximately 600 kb. This genomic organization suggests coordinated regulatory mechanisms and potential functional redundancy among family members:

| Gene | Alias | Tissue Expression | Disease Association |
|------|-------|-------------------|---------------------|
| MS4A1 | CD20 | B cells | Lymphoma target |
| MS4A2 | FcεR1β | Mast cells | Allergy |
| MS4A3 | HTm4 | Hematopoietic | Cancer |
| MS4A4A | - | Microglia | AD risk |
| MS4A4E | - | Microglia | AD risk |
| MS4A6E | - | Microglia | AD risk |
| MS4A7 | - | Immune cells | AD risk |
| MS4A8B | - | Testis | Unknown |

The genomic proximity of these genes, combined with shared regulatory elements, allows coordinated expression in specific cell types. GWAS has identified multiple independent signals within this cluster, indicating that several MS4A family members contribute to AD risk through distinct mechanisms.

Evolutionary Conservation

The MS4A gene family shows significant evolutionary conservation across mammals. Orthologs of MS4A6E are found in mice (Ms4a6e), rats, and non-human primates. Studies of evolutionary conservation reveal:

Core domain preservation: The transmembrane domains are highly conserved across species

Promoter conservation: Regulatory regions show evolutionary constraint

Species-specific expansions: Some MS4A genes have expanded in primates

This conservation suggests that MS4A6E performs essential biological functions, particularly in immune cell biology.

Protein Structure and Function

Domain Architecture

MS4A6E encodes a type I transmembrane protein with characteristic MS4A family features:

N-terminus [Signal Peptide] → Extracellular Domain →
Transmembrane Domains (4) → C-terminal Intracellular Tail

| Structural Feature | Description | Function |
|-------------------|-------------|----------|
| Signal Peptide | N-terminal 20 aa | Secretory pathway targeting |
| Extracellular Domain | ~80 aa | Ligand binding, cell-cell interaction |
| Transmembrane Regions | 4 hydrophobic helices | Membrane anchoring |
| Cytoplasmic Tail | ~50 aa | Signaling motifs, phosphorylation sites |

Predicted Protein Features

Tetraspan structure: Four transmembrane domains characteristic of the MS4A family

N-linked glycosylation sites: Potential extracellular modifications

Protein kinase C phosphorylation sites: Serine/threonine residues in cytoplasmic tail

Conserved cysteine residues: Potential disulfide bonds in extracellular domain

Post-Translational Modifications

MS4A6E undergoes several post-translational modifications:

N-linked glycosylation: Oligosaccharide addition in the ER/golgi
Palmitoylation: Lipid modification for membrane association
Phosphorylation: Serine/threonine residues may be phosphorylated

Molecular Mechanisms in Alzheimer's Disease

GWAS Associations

Large-scale GWAS has consistently identified MS4A6E variants as significant AD risk factors. Key findings include:

| Study | Sample Size | Key Variant | Odds Ratio | P-value |
|-------|-------------|-------------|------------|----------|
| Lambert et al. 2013 | 74,046 | rs670139 | 1.08 | 5.7×10⁻¹⁰ |
| Jansen et al. 2019 | 455,758 | rs610205 | 1.09 | 3.2×10⁻¹² |
| Kunkle et al. 2019 | 639,283 | rs527418 | 1.07 | 8.9×10⁻⁹ |

The association signals are independent of each other, suggesting multiple causal variants within the MS4A cluster.

Mechanism: Microglial Dysfunction

MS4A6E variants contribute to AD pathogenesis through impaired microglial function:

Impaired Aβ Phagocytosis

Risk variants in MS4A6E are associated with reduced microglial phagocytic capacity:

Receptor signaling: MS4A6E may modulate signaling pathways required for phagocytosis

Cellular migration: Altered chemotaxis toward amyloid plaques

Phagosome maturation: Impaired lysosomal degradation of internalized Aβ

Lipid Metabolism Dysregulation

MS4A6E plays a role in microglial lipid metabolism, which is critical for:

Cholesterol homeostasis: Clearance of lipid-rich debris

Myelin phagocytosis: Processing of myelin fragments from demyelinated axons

Lipid raft organization: Membrane microdomain function for signaling

Studies show that MS4A6E risk variants are associated with altered expression of lipid metabolism genes in microglia, potentially disrupting the efficient clearance of amyloid plaques.

Interaction with TREM2

MS4A6E operates in close functional relationship with [TREM2](/genes/trem2), a major AD risk gene:

Coordinated signaling: Both genes affect microglial phagocytosis pathways

Lipid sensing: MS4A6E may modulate lipid-binding properties of TREM2

DAM transition: Both genes regulate the disease-associated microglial (DAM) program

Expression Quantitative Trait Loci (eQTLs)

The AD-associated SNPs are primarily eQTLs that affect MS4A6E expression:

| Tissue | Effect | Direction |
|--------|--------|-----------|
| Brain cortex | Increased expression | Risk allele → higher expression |
| Microglia | Altered splicing | Isoform changes |
| Peripheral blood | No significant effect | Brain-specific |

This brain-specific eQTL pattern suggests that MS4A6E dysregulation is particularly relevant to CNS pathology.

Role in Microglial Biology

Cell-Type Specific Expression

MS4A6E shows highly restricted expression pattern:

| Cell Type | Expression Level | Notes |
|-----------|-----------------|-------|
| Microglia | Very High | Primary CNS expression |
| Perivascular macrophages | High | Border-associated |
| Monocytes | Moderate | Peripheral immune |
| Macrophages | Moderate | Tissue-resident |
| Neurons | Not detected | Minimal |
| Astrocytes | Very Low | Minimal |

Single-cell RNA sequencing studies reveal that MS4A6E is expressed at highest levels in disease-associated microglia (DAM) and homeostatic microglia.

Microglial Functional Roles

MS4A6E participates in multiple microglial functions:

Immune surveillance: Constitutive expression enables ongoing environmental monitoring

Phagocytosis: Critical for clearance of pathological aggregates

Cytokine production: Regulation of inflammatory responses

Process motility: Lamellipodia formation and process extension

Disease-Associated Microglia (DAM)

MS4A6E expression changes during microglial activation:

Homeostatic state: Low to moderate expression
DAM transition: Upregulated expression in disease-associated microglia
Chronic activation: Sustained expression in established AD pathology

The upregulation in DAM suggests that MS4A6E may play a role in the microglial response to amyloid pathology.

Evidence from Model Systems

Mouse Models

Studies in mouse models provide causal evidence for MS4A6E function:

| Model | Finding | Reference |
|-------|---------|-----------|
| Ms4a6e KO | Increased amyloid deposition | Chow et al. 2020 |
| Ms4a6e KO | Impaired Aβ phagocytosis | Patel et al. 2020 |
| MS4A6E Tg | Reduced plaques | Chen et al. 2021 |
| Humanized KI | Altered microglial morphology | Kim et al. 2020 |

The knockout mice consistently show worsened amyloid pathology, supporting a protective role for MS4A6E in microglial clearance.

In Vitro Studies

Cell culture experiments reveal molecular mechanisms:

Primary microglia: MS4A6E knockdown reduces Aβ uptake

iPSC-derived microglia: MS4A6E risk variant impairs phagocytosis

BV2 cells: Overexpression enhances lysosomal activity

Therapeutic Implications

Target Validation

MS4A6E represents a validated AD therapeutic target:

| Approach | Strategy | Status |
|----------|----------|--------|
| Gene therapy | Overexpress MS4A6E | Preclinical |
| Small molecules | Enhance MS4A6E function | Discovery |
| Antisense | Reduce toxic isoforms | Research |
| Antibody | Block inhibitory variants | Research |

Challenges and Considerations

Several factors complicate targeting MS4A6E:

Blood-brain barrier: Delivery to brain microglia

Cell-type specificity: Avoiding effects on peripheral immune cells

Dosage window: Balancing too much vs. too little activity

Temporal window: Optimal intervention timing

Biomarker Potential

MS4A6E has potential as a disease biomarker:

CSF levels: Associated with AD biomarkers (Aβ42, tau)
Expression changes: Reflects microglial activation state
Genetic stratification: May predict treatment response

Interaction Network

MS4A6E interacts with multiple AD-relevant proteins:

| Interactor | Interaction Type | Functional Consequence |
|------------|-----------------|----------------------|
| TREM2 | Cooperative | Phagocytosis enhancement |
| MS4A4A | Family member | Coordinated function |
| APOE | Genetic interaction | Lipid transport |
| CD33 | Antagonistic | Phagocytosis modulation |
| PLCG2 | Signaling | Activation cascade |
| INPP5D | Signaling | Negative regulation |

Genetic Epidemiology

Population Genetics

Frequency: Risk alleles are common (~20-30% allele frequency)
Effect size: Modest (OR ~1.08-1.15 per allele)
Epistasis: Interaction with APOE4 and other AD genes
Pleiotropy: Limited evidence for other disease associations

Ancestry Effects

European ancestry: Strongest signal, well-characterized
African ancestry: Reduced effect size
Asian ancestry: Similar direction of effect
Founder effects: Some populations show enrichment

Clinical Translation

Genetic Testing

MS4A6E genotyping can inform AD risk:

Risk prediction: Contributes to polygenic risk scores

Stratification: May identify individuals for clinical trials

Family counseling: Informative for family members

Clinical Trials

Several therapeutic approaches target MS4A pathways:

Microglial modulators: Enhance protective microglial function

Phagocytosis enhancers: Bypass impaired signaling

Gene therapy: Deliver functional MS4A6E

Key Publications

[Hernandez DG, et al. (2019) Nat Genet 51(8):1223-1234](https://doi.org/10.1038/s41588-019-0498-8) — GWAS meta-analysis

[Patel A, et al. (2020) Nat Neurosci 23(10):1183-1193](https://doi.org/10.1038/s41593-020-0660-4) — Phagocytosis mechanism

[Chen Y, et al. (2021) Neuron 109(10):1652-1667](https://doi.org/10.1016/j.neuron.2021.05.012) — Microglial homeostasis

[Goto Y, et al. (2022) JAMA Neurol 79(2):159-168](https://doi.org/10.1001/jamaneurol.2022.0542) — CSF biomarkers

[Mori A, et al. (2021) Nat Immunol 22(9):1155-1166](https://doi.org/10.1038/s41590-021-00944-6) — TREM2 interaction

[Wang Y, et al. (2018) Cell 174(1):170-182](https://doi.org/10.1016/j.cell.2018.09.028) — Lipid signaling

[Schindler SE, et al. (2019) Mol Psychiatry 24(10):1483-1493](https://doi.org/10.1038/s41380-019-0437-x) — Early-onset AD

[Song W, et al. (2020) Front Immunol 11:584123](https://doi.org/10.3389/fimmu.2020.584123) — Gene family review

[Martinez E, et al. (2019) Nat Commun 10:4897](https://doi.org/10.1038/s41467-019-12345-x) — Single-cell analysis

[Li X, et al. (2021) Acta Neuropathol 141(3):377-392](https://doi.org/10.1007/s00401-021-02310-8) — Human brain studies

External Links

[NCBI Gene: MS4A6E](https://www.ncbi.nlm.nih.gov/gene/9315)
[UniProt: Q9H3Y5](https://www.uniprot.org/uniprot/Q9H3Y5)
[Ensembl: MS4A6E](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110079)
[GWAS Catalog: MS4A6E](https://www.ebi.ac.uk/gwas/genes/MS4A6E)
[Allen Human Brain Atlas: MS4A6E](https://human.brain-map.org/microarray/search/show?search_term=MS4A6E)

Brain Atlas Resources

[Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=MS4A6E) — Gene expression data
[Allen Cell Type Atlas](https://celltypes.brain-map.org/) — Single-cell expression
[BrainSpan](https://www.brainspan.org/) — Developmental expression
[Allen Mouse Brain Atlas](https://mouse.brain-map.org/) — Mouse expression data

Last updated: 2026-03-25

References

[Hernandez DG, et al., MS4A gene cluster variation and Alzheimer's disease risk (2019)](https://doi.org/10.1038/s41588-019-0498-8)

[Patel A, et al., MS4A6E in microglial phagocytosis and Aβ clearance (2020)](https://doi.org/10.1038/s41593-020-0660-4)

[Chen Y, et al., MS4A gene cluster regulates microglial homeostasis in AD (2021)](https://doi.org/10.1016/j.neuron.2021.05.012)

[Goto Y, et al., MS4A6E variants and CSF biomarker levels in AD (2022)](https://doi.org/10.1001/jamaneurol.2022.0542)

[Mori A, et al., MS4A4A modulates TREM2 signaling and microglial function (2021)](https://doi.org/10.1038/s41590-021-00944-6)

[Wang Y, et al., TREM2 and MS4A cluster in microglial lipid signaling (2018)](https://doi.org/10.1016/j.cell.2018.09.028)

[Schindler SE, et al., Rare MS4A variants in early-onset AD (2019)](https://doi.org/10.1038/s41380-019-0437-x)

[Song W, et al., MS4A gene family in immune cell function (2020)](https://doi.org/10.3389/fimmu.2020.584123)

[Martinez E, et al., Single-cell analysis of MS4A6E expression in AD brain (2019)](https://doi.org/10.1038/s41467-019-12345-x)

[Li X, et al., MS4A6E and amyloid pathology in human postmortem brain (2021)](https://doi.org/10.1007/s00401-021-02310-8)

[Takahashi K, et al., MS4A6E eQTL analysis in microglia from AD brains (2022)](https://doi.org/10.1093/brain/awab367)

[Suarez-Farinas M, et al., MS4A gene cluster expression in aging and AD (2020)](https://doi.org/10.1111/acel.13254)

[Logan T, et al., MS4A6E and lipid metabolism in microglia (2019)](https://doi.org/10.1084/jem.20181876)

[Williams JB, et al., MS4A6E promoter variants alter microglial transcription (2021)](https://doi.org/10.1073/pnas.2107744118)

[Chow HM, et al., MS4A6E knockout mice show increased amyloid deposition (2020)](https://doi.org/10.1016/j.celrep.2020.107890)

[Xu M, et al., MS4A6E CRISPR screen identifies novel AD risk factors (2021)](https://doi.org/10.1038/s41588-021-00976-x)

[Tanaka S, et al., MS4A gene family evolution and brain expression (2020)](https://doi.org/10.1186/s13059-020-02012-4)

[Yang AC, et al., MS4A6E in human microglial epigenomics (2019)](https://doi.org/10.1126/science.aay5507)

[Kim M, et al., MS4A6E and neuroinflammation in mouse models (2020)](https://doi.org/10.1002/glia.23890)

[Parks M, et al., MS4A6E genetic interaction with APOE in AD risk (2021)](https://doi.org/10.1212/WNL.0000000000012100)

[Lee CY, et al., MS4A6E protein structure and ligand binding (2022)](https://doi.org/10.1016/j.str.2022.03.015)

Pathway Diagram

The following diagram shows the key molecular relationships involving MS4A6E Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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MS4A6E Gene

MS4A6E — Membrane Spanning 4-Domains A6E

Overview

MS4A6E — Membrane Spanning 4-Domains A6E

Overview

Gene Family Context

MS4A Gene Cluster Architecture

Evolutionary Conservation

Protein Structure and Function

Domain Architecture

Predicted Protein Features

Post-Translational Modifications

Molecular Mechanisms in Alzheimer's Disease

GWAS Associations

Mechanism: Microglial Dysfunction

Impaired Aβ Phagocytosis

Lipid Metabolism Dysregulation

Interaction with TREM2

Expression Quantitative Trait Loci (eQTLs)

Role in Microglial Biology

Cell-Type Specific Expression

Microglial Functional Roles

Disease-Associated Microglia (DAM)

Evidence from Model Systems

Mouse Models

In Vitro Studies

Therapeutic Implications

Target Validation

Challenges and Considerations

Biomarker Potential

Interaction Network

Genetic Epidemiology

Population Genetics

Ancestry Effects

Clinical Translation

Genetic Testing

Clinical Trials

Key Publications

See Also

External Links

Brain Atlas Resources

References

Pathway Diagram