AR (Androgen Receptor) Gene: Structure, Function, and Clinical Significance
A comprehensive overview of the androgen receptor gene, its role in physiology and disease, and its implications for targeted therapies.
Gene Information Card
| Symbol | AR |
|---|---|
| Full Name | Androgen Receptor |
| Gene Type | Protein coding |
| Chromosomal Location | Xq12 |
| NCBI Gene ID | 367 ncbi.nlm.nih.gov/gene/367 |
| Ensembl ID | ENSG00000169083 |
| UniProt ID | P10275 |
| OMIM ID | 313700 |
| HGNC ID | 644 |
| Aliases | NR3C4, DHTR, HUMARA, AIS, SBMA, KD, TFM |
Description
The AR gene encodes the androgen receptor, a ligand-activated nuclear transcription factor that mediates the effects of androgens (testosterone and dihydrotestosterone) in target tissues. It plays a critical role in male sexual differentiation, development, and maintenance of male reproductive tissues, as well as in non-reproductive tissues like muscle, bone, and brain. Mutations and dysregulation of AR are associated with various conditions, including androgen insensitivity syndrome, spinal bulbar muscular atrophy (Kennedy disease), and prostate cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Prostate Cancer | AR signaling promotes tumor growth; mutations and amplifications lead to constitutive activation or altered ligand specificity, driving resistance to anti-androgen therapy. | ClinVar, COSMIC, OMIM |
| Androgen Insensitivity Syndrome (AIS) | Loss-of-function mutations in AR impair androgen signaling, leading to varying degrees of feminization in 46,XY individuals. | ClinVar, OMIM |
| Spinal Bulbar Muscular Atrophy (SBMA) | Expansion of a CAG repeat in the AR gene results in a polyglutamine tract, causing toxic gain-of-function and motor neuron degeneration. | OMIM, ClinVar |
| Breast Cancer | AR expression is variable; in some subtypes, AR signaling may promote or inhibit tumor growth, depending on context. | COSMIC, ClinVar |
| Hypogonadism | AR mutations can cause partial androgen insensitivity, leading to undervirilization and hypogonadism in males. | ClinVar, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Prostate | High | High expression |
| Testis | Medium | Moderate expression |
| Adrenal Gland | Medium | Moderate expression |
| Liver | Low | Low expression |
| Brain | Low | Low expression |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| LNCaP (Prostate Cancer) | High | AR-positive; androgen-responsive |
| PC3 (Prostate Cancer) | Low | AR-negative; androgen-independent |
| MCF7 (Breast Cancer) | Low | ER-positive; AR expression variable |
| HepG2 (Liver Cancer) | Low | Low AR expression |
| HeLa (Cervical Cancer) | Low | Low AR expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Arg841Gly | Missense | Rare | Ligand-binding domain; associated with partial androgen insensitivity |
| p.Pro390Ser | Missense | Rare | DNA-binding domain; affects transcriptional activity |
| CAG repeat expansion (polyQ) | Repeat expansion | Variable | Toxic gain-of-function; causes SBMA |
| p.Thr877Ala | Missense | Somatic in prostate cancer | Constitutive activation; promotes anti-androgen resistance |
| p.Trp741Cys | Missense | Somatic in prostate cancer | Alters ligand specificity; allows activation by anti-androgens |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in AR impair androgen binding or transcriptional activity, leading to androgen insensitivity syndrome (AIS) with phenotypes ranging from mild undervirilization to complete female external genitalia.
Gain of Function (GOF)
Gain-of-function mutations, such as those in prostate cancer, confer constitutive activity or broaden ligand specificity, promoting tumor growth and resistance to therapy.
Dominant Negative (DN)
Some AR mutations may exert dominant-negative effects by forming inactive heterodimers with wild-type receptors, reducing overall androgen signaling.
View complete mutation data：
Gene Ontology (GO)
| • DNA-binding transcription factor activity | • RNA polymerase II cis-regulatory region sequence-specific DNA binding |
| • zinc ion binding | • steroid hormone receptor activity |
| • androgen binding | • chromatin binding |
| • protein heterodimerization activity | • transcription coactivator binding |
| • ubiquitin protein ligase binding | • signal transducer activity |
Pathways
• Androgen receptor signaling pathway
• Prostate cancer pathway
• Nuclear receptor transcription pathway
• Signaling by nuclear receptors
• Regulation of gene expression by steroid hormones
Protein Summary
The androgen receptor (AR) is a 110 kDa nuclear receptor composed of an N-terminal regulatory domain, a DNA-binding domain (DBD), a hinge region, and a ligand-binding domain (LBD). Upon binding androgens, AR translocates to the nucleus, homodimerizes, and binds to androgen response elements (AREs) in target gene promoters, recruiting coactivators to modulate transcription. AR also has non-genomic actions, activating kinase signaling cascades. Post-translational modifications (phosphorylation, acetylation, ubiquitination) regulate its stability and activity. In prostate cancer, AR signaling is a key driver, and therapies targeting AR are central to treatment.
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