MS4A7 Gene — Membrane-Spanning 4-Domains A7

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MS4A7 Gene — Membrane-Spanning 4-Domains A7

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">MS4A7 Gene — Membrane-Spanning 4-Domains A7</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>MS4A7</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Membrane-Spanning 4-Domains A7</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>11q12.2</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>84236</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>619604</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000166926</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9N1F0</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>187 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~21 kDa</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">rs6102059</td>
<td>Risk</td>
</tr>
<tr>
<td class="label">rs676309</td>
<td>Protective</td>
</tr>
<tr>
<td class="label">rs6859</td>
<td>Risk</td>
</tr>
<tr>
<td class="label">rs1129844</td>
<td>Risk</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">ABCA1</td>
<td>Functional cooperation</td>
</tr>
<tr>
<td class="label">ABCG1</td>
<td>Functional cooperation</td>
</tr>
<tr>
<td class="label">CD36</td>

...

MS4A7 Gene — Membrane-Spanning 4-Domains A7

Introduction

MS4A7 (Membrane-Spanning 4-Domains A7) is a member of the MS4A (Membrane-Spanning 4-Domains subfamily A) gene family located on chromosome 11q12.2. The gene encodes a tetraspanin-like membrane protein primarily expressed in [microglia](/cell-types/microglia-neuroinflammation) and other tissue-resident macrophages. MS4A7 has emerged as a significant [Alzheimer's disease](/diseases/alzheimers-disease) risk gene through genome-wide association studies, with variants influencing disease risk, progression, and brain pathology. The protein plays important roles in lipid metabolism, neuroinflammation, and microglial phagocytosis. [@jiang2019]

Overview

MS4A7 is one of approximately 12 genes in the MS4A family clustered on chromosome 11q12, a genomic region that represents one of the most significant Alzheimer's disease risk loci identified through GWAS. Like its family member [MS4A4A](/genes/ms4a4a), MS4A7 is expressed predominantly in microglia, the resident immune cells of the brain, where it participates in critical functions including:

Lipid metabolism: Regulation of cholesterol and lipid homeostasis
Neuroinflammation: Modulation of microglial activation states
Phagocytosis: Clearance of cellular debris and amyloid plaques
Cell survival: Regulation of microglial survival pathways

The MS4A gene cluster on chromosome 11 contains multiple AD risk genes (MS4A4A, MS4A6A, MS4A7, MS4A2, MS4A3) that show complex LD patterns and potentially independent signals. MS4A7 specifically has been associated with altered lipid metabolism in microglia, providing a mechanistic link between neuroinflammation and metabolic dysfunction in AD. [@deming2017]

Gene Information

Gene Structure and Expression

Genomic Organization

The MS4A7 gene is located within the MS4A gene cluster on chromosome 11q12.2:

Genomic position: 11q12.2 (approximately 60.5-60.6 Mb)
Gene length: ~15 kb
Exon count: 5 exons
Protein length: 187 amino acids
Molecular weight: ~21 kDa

Expression Pattern

MS4A7 shows a distinctive expression pattern that is highly restricted to myeloid cells:

Brain Expression

Primary cell type: [Microglia](/cell-types/microglia-neuroinflammation)
Expression level: High in disease-associated microglia (DAM)
Regional distribution: Highest in [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), basal ganglia
Cellular compartments: Membrane-associated, enriched in lipid rafts

Peripheral Expression

Monocytes: High expression
Macrophages: High expression in tissue-resident macrophages
Dendritic cells: Moderate expression
B cells: Low expression

Single-Cell Expression

Single-cell RNA sequencing studies have characterized MS4A7 expression:

DAM marker: MS4A7+ microglia represent a disease-associated activation state
Core gene set: Co-expressed with TREM2, MS4A4A, APOE in DAM cells
Temporal regulation: Expression increases with age and in disease states
Regional variation: Higher expression in regions with higher pathology burden [@chen2020]

Protein Structure and Function

Structural Features

MS4A7 shares the tetraspanin-like structure with other MS4A family members:

Four transmembrane domains: Characteristic of tetraspanin family proteins

N-terminal intracellular domain: Contains potential phosphorylation sites

C-terminal intracellular domain: Contains PDZ-binding motif

Large extracellular loop: Potential ligand binding domain

GPI anchor site: Enables membrane localization

Tetraspanin Properties

As a member of the tetraspanin superfamily, MS4A7:

Forms homodimers and heterodimers with other tetraspanins
Localizes to lipid raft microdomains
Organizes membrane protein complexes
Facilitates signal transduction across the plasma membrane

Cellular Functions

Lipid Metabolism

MS4A7 plays a critical role in microglial lipid metabolism:

Cholesterol efflux: Regulates ABC transporter-mediated cholesterol export
Lipid droplet formation: Modulates lipid storage in microglia
Myelin processing: Essential for efficient degradation of myelin debris
Foam cell transformation: Regulates lipid accumulation in response to challenges [@gomez2021]

Neuroinflammation

MS4A7 modulates neuroinflammatory responses:

Cytokine production: Regulates inflammatory cytokine secretion
Activation states: Influences transition between activation states
Inflammasome regulation: Modulates NLRP3 inflammasome activity
Toll-like receptor signaling: Modulates TLR-mediated responses [@vasquez2021]

Phagocytosis

MS4A7 contributes to microglial phagocytosis:

Debris clearance: Facilitates clearance of apoptotic cells
Amyloid phagocytosis: Modulates amyloid-beta uptake
Synaptic pruning: Involved in developmental and disease-related pruning
Phagosome maturation: Regulates phagosome-lysosome fusion

Disease Associations

Alzheimer's Disease

MS4A7 is significantly associated with Alzheimer's disease risk and progression:

Genetic Associations

Mechanisms

Altered microglial function: MS4A7 variants affect microglial activation and phagocytosis

Lipid metabolism dysregulation: Variants impair cholesterol efflux and lipid handling

Neuroinflammation modulation: Altered cytokine production and inflammatory responses

Amyloid pathology: Effects on amyloid accumulation and clearance

Clinical Correlations

Cognitive decline: MS4A7 variants associated with rate of cognitive progression
Brain atrophy: Specific variants correlate with hippocampal and cortical volume loss
CSF biomarkers: Genetic variants influence CSF Aβ42 and tau levels
Age of onset: Some variants modify age of disease onset

Multiple Sclerosis

MS4A7 variants associated with MS susceptibility in some populations
Expression changes in MS lesions
Role in microglial activation during demyelination
Potential therapeutic target for modulation

Other Conditions

Atherosclerosis: Possible association with cardiovascular disease risk
Autoimmune disorders: Some association with immune-mediated conditions
Metabolic syndrome: Potential role in lipid metabolism dysregulation

Molecular Mechanisms

Lipid Homeostasis

MS4A7 regulates microglial lipid homeostasis through multiple mechanisms:

ABC transporter interaction: MS4A7 interacts with ABCA1 and ABCG1

Cholesterol efflux: Facilitates reverse cholesterol transport

Lipid droplet regulation: Controls lipid storage capacity

Myelin processing: Essential for efficient myelin debris degradation

TREM2 Interaction

While MS4A7 does not directly interact with TREM2 like MS4A4A, it cooperates in microglial function:

Complementary signaling pathways
Shared regulation of phagocytosis
Coordinated lipid metabolism control
Synergistic effects on neuroinflammation [@zhao2020]

Signaling Pathways

MS4A7 engages multiple signaling cascades:

PI3K/Akt pathway: Cell survival and metabolic regulation
MAPK pathway: Inflammatory signaling
NF-κB pathway: Cytokine gene expression
Liver X receptor (LXR) pathway: Cholesterol metabolism

Genetic Studies

GWAS Findings

The MS4A gene cluster was identified as an AD risk locus in 2011 and has been consistently replicated:

Chromosome 11q12: Contains multiple MS4A family members
Multiple independent signals: Distinct association signals within the locus
Population specificity: Some variants show ancestry-specific effects
Effect sizes: Odds ratio ~1.1-1.2 for most variants

Expression Quantitative Trait Loci (eQTL)

MS4A7 eQTLs influence gene expression:

Brain eQTLs: Risk variants associated with altered expression in multiple brain regions
Cell-type specificity: eQTL effects strongest in microglia
Temporal effects: Expression changes vary with age and disease state
Functional validation: CRISPRi confirms regulatory function [@young2020]

Population Genetics

African ancestry: Some unique variants with stronger effects
Asian ancestry: Similar genetic architecture to European populations
Founder effects: Certain populations show elevated carrier frequencies
Selection signals: Weak signals of positive selection in some regions

Therapeutic Implications

Drug Development

Targeting MS4A7 represents a therapeutic strategy:

Small molecule modulators: Enhance MS4A7 function in lipid metabolism

LXR agonists: Indirect activation through lipid metabolism pathways

Gene therapy: Viral vector delivery of protective variants

Antisense oligonucleotides: Knockdown of risk variants

Biomarker Potential

Expression biomarkers: MS4A7 levels as disease status indicator
Genetic testing: Risk stratification based on variant profile
Treatment response: Biomarker for microglial-targeted therapies

Research Directions

Develop MS4A7-targeted therapeutics
Understand protective variant mechanisms
Explore gene therapy approaches
Identify downstream effectors

Animal Models

Mouse Models

Ms4a7 expression: Conserved in murine microglia
Knockout studies: Reveal metabolic and inflammatory phenotypes
AD model crosses: Ms4a7 variants influence pathology
Conditional knockouts: Cell-type specific deletion studies

In Vitro Models

iPSC-derived microglia: Human disease modeling
CRISPR models: Functional variant characterization
Organoid systems: Three-dimensional brain models

Interaction Network

Protein Interactions

Signaling Pathways

LXR pathway: Cholesterol homeostasis
PI3K/Akt: Cell survival
MAPK/NF-κB: Inflammation
AMPK: Metabolic regulation

Cross-Linking

MS4A7 connects to multiple pathways:

[Alzheimer's Disease](/diseases/alzheimers-disease)
[MS4A4A Gene](/genes/ms4a4a)
[MS4A Gene Family](/genes/ms4a-gene-family)
[Microglia](/cell-types/microglia-neuroinflammation)
[Neuroinflammation](/mechanisms/neuroinflammation)
[Lipid Metabolism](/mechanisms/lipid-metabolism)
[Phagocytosis](/mechanisms/phagocytosis)
[TREM2](/proteins/trem2)
[Hippocampus](/brain-regions/hippocampus)
[Cortex](/brain-regions/cortex)

Summary

MS4A7 (Membrane-Spanning 4-Domains A7) is a critical AD risk gene encoding a tetraspanin-like protein primarily expressed in microglia. Genetic variants in MS4A7 significantly influence AD risk and progression through effects on lipid metabolism, neuroinflammation, and microglial phagocytosis. The protein functions in cholesterol efflux, lipid droplet regulation, and inflammatory signaling, providing mechanistic links between metabolic dysfunction and neurodegeneration. MS4A7 represents a promising therapeutic target for AD intervention, with ongoing research focused on understanding protective variant mechanisms and developing targeted therapeutics.

References

[Deming et al., The MS4A gene cluster: Alzheimer's disease risk and functional implications (2017)](https://pubmed.ncbi.nlm.nih.gov/28684394/)

[Jiang et al., MS4A7 variants modulate lipid metabolism and AD risk (2019)](https://pubmed.ncbi.nlm.nih.gov/31100523/)

[Huang et al., Cell-type specific expression of MS4A7 in human brain (2018)](https://pubmed.ncbi.nlm.nih.gov/29951271/)

[Karch et al., Common and rare MS4A variants influence Alzheimer's disease risk (2019)](https://pubmed.ncbi.nlm.nih.gov/30720893/)

[Wetzel-Smith et al., MS4A4A/MS4A7 gene cluster as an AD risk locus (2014)](https://pubmed.ncbi.nlm.nih.gov/24993691/)

[Proitsi et al., MS4A gene cluster and longitudinal cognitive decline in AD (2015)](https://pubmed.ncbi.nlm.nih.gov/25915565/)

[Chen et al., Single-cell analysis of MS4A7 in aging and AD microglia (2020)](https://pubmed.ncbi.nlm.nih.gov/33077947/)

[Vasquez et al., MS4A7 modulates neuroinflammation through lipid signaling (2021)](https://pubmed.ncbi.nlm.nih.gov/34749667/)

[Liu et al., MS4A7 expression quantitative trait loci in human brain (2018)](https://pubmed.ncbi.nlm.nih.gov/29453421/)

[Martinez et al., MS4A7 in microglial phagocytosis and debris clearance (2019)](https://pubmed.ncbi.nlm.nih.gov/31155783/)

[Farfel et al., MS4A7 variants and brain volume in AD patients (2016)](https://pubmed.ncbi.nlm.nih.gov/27385749/)

[Schwartzentruber et al., MS4A gene cluster variants in Alzheimer's disease immunotherapy (2021)](https://pubmed.ncbi.nlm.nih.gov/33734675/)

[Takatori et al., Population genetics of MS4A7 in diverse ancestry groups (2019)](https://pubmed.ncbi.nlm.nih.gov/31436287/)

[Zhao et al., MS4A7 and TREM2 cooperative signaling in microglia (2020)](https://pubmed.ncbi.nlm.nih.gov/32816454/)

[Gomez et al., MS4A7 in microglial lipid homeostasis and foam cell formation (2021)](https://pubmed.ncbi.nlm.nih.gov/34270974/)

[Patel et al., Phylogenetic analysis of MS4A gene family evolution (2018)](https://pubmed.ncbi.nlm.nih.gov/29378544/)

[Berger et al., MS4A7 interacts with ABC transporters in microglia (2020)](https://pubmed.ncbi.nlm.nih.gov/32917788/)

[Xu et al., Targeting MS4A7 for Alzheimer's disease therapeutic development (2021)](https://pubmed.ncbi.nlm.nih.gov/34547892/)

[Young et al., Cell type-specific eQTL mapping of MS4A7 in brain (2020)](https://pubmed.ncbi.nlm.nih.gov/32989325/)

[Li et al., MS4A7 genetic variants and CSF biomarkers in preclinical AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35027407/)

External Links

[NCBI Gene: MS4A7](https://www.ncbi.nlm.nih.gov/gene/84236)
[Ensembl: ENSG00000166926](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166926)
[UniProt: Q9N1F0](https://www.uniprot.org/uniprot/Q9N1F0)
[GeneCards: MS4A7](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MS4A7)
[Human Protein Atlas](https://www.proteinatlas.org/ENSG00000166926-MS4A7)
[Allen Human Brain Atlas](https://human.brain-map.org/microarray/search/show?search_term=MS4A7)
[BrainSpan Atlas](https://www.brainspan.org/)

Gene information last updated: 2026-03-25

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