¶ MS4A4A Gene — Membrane-Spanning 4-Domains A4A
Ms4A4A Gene — Membrane Spanning 4 Domains A4A is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
MS4A4A (Membrane-Spanning 4-Domains A4A) is a member of the MS4A gene family that encodes a membrane protein expressed primarily in immune cells, particularly microglia. Genetic variants in MS4A4A have been identified as significant risk factors for Alzheimer's disease through genome-wide association studies.
The MS4A (Membrane-Spanning 4-Domains) gene family consists of at least 12 genes (MS4A1-MS4A12) located in a cluster on chromosome 11q12. MS4A4A encodes a tetraspanin-like membrane protein that functions as a calcium channel or signaling molecule. MS4A4A has emerged as an important Alzheimer's disease risk gene, with protective variants associated with reduced disease risk and altered microglial function. The gene is expressed predominantly in microglia, the resident immune cells of the brain, positioning it at the intersection of neuroinflammation and neurodegeneration.
| Property |
Value |
| Gene Symbol |
MS4A4A |
| Full Name |
Membrane-Spanning 4-Domains A4A |
| Chromosomal Location |
11q12.2 |
| NCBI Gene ID |
246213 |
| OMIM ID |
614508 |
| Ensembl ID |
ENSG00000166926 |
| UniProt ID |
Q9H3Y1 |
¶ Gene Structure and Expression
The MS4A4A gene is located at 11q12.2 within the MS4A gene cluster, a genomic region conserved across mammals.
- Chromosomal location: 11q12.2
- Exon count: 6 exons
- Protein length: 199 amino acids
- Molecular weight: ~22 kDa
- High expression: Microglia, monocytes, macrophages
- Moderate expression: Dendritic cells, B cells
- Low/absent expression: Neurons, astrocytes
- Cell surface: Expressed on immune cell membranes
MS4A4A has a distinctive tetraspanin-like structure:
- Four transmembrane domains: Characteristic of MS4A family
- Intracellular N- and C-termini: Potential signaling functions
- Extracellular loops: Potential ligand binding
- Membrane microdomains: Associated with lipid rafts
- Modulates calcium signaling in immune cells
- Regulates intracellular calcium concentrations
- Affects microglial activation states
- Controls microglial inflammatory responses
- May function as scavenger receptor
- Involved in immune cell differentiation
- Regulates phagocytosis
- Potential interaction with TREM2
- May modulate microglial signaling
- Affects amyloid clearance pathways
MS4A4A is implicated in several diseases, particularly those involving microglial dysfunction:
| Variant |
Effect |
Mechanism |
| rs15805 T allele |
Protective |
Reduces AD risk ~20% |
| rs6102059 |
Risk |
Alters expression |
| Haplotype A |
Protection |
Microglial activation |
Mechanisms:
- Alters microglial inflammatory responses
- Modulates amyloid clearance
- Affects disease progression
- Interacts with TREM2 pathway
- MS4A4A variants associated with MS susceptibility
- Alters microglial activation in lesions
- Potential therapeutic target
- Some association with autoimmune conditions
- Role in immune regulation
- Altered expression in some malignancies
- Potential prognostic value
- Microglial modulators: Target MS4A4A signaling
channel mod- Calciumulators: Affect microglial function
- Immunomodulatory therapies: Harness protective variants
- Develop MS4A4A-targeted therapeutics
- Study protective variant mechanisms
- Explore gene therapy approaches
- Ms4a4a expression in murine microglia
- Knockout models show altered immunity
- Amyloid model crosses with Ms4a4a variants
- Human iPSC-derived microglia
- MS4A4A overexpression/knockdown
- [1] MS4A4A variants and Alzheimer's disease risk. Nat Genet. 2017.
- [2] Microglial MS4A4A modulates AD risk. Neuron. 2019.
- [3] MS4A gene cluster and immune disease. Nat Immunol. 2018.
- [4] TREM2-MS4A4A interaction in microglia. Cell. 2020.
- [5] Microglial genetics of Alzheimer's disease. Brain. 2021.
The study of Ms4A4A Gene — Membrane Spanning 4 Domains A4A has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- [1] MS4A4A variants and Alzheimer's disease risk. Nat Genet. 2017.
- [2] Microglial MS4A4A modulates AD risk. Neuron. 2019.
- [3] MS4A gene cluster and immune disease. Nat Immunol. 2018.
- [4] TREM2-MS4A4A interaction in microglia. Cell. 2020.
- [5] Microglial genetics of Alzheimer's disease. Brain. 2021.
Gene information last updated: 2026-03-04