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AR
androgen receptor
The AR gene provides instructions for the androgen receptor protein, which is vital for male sexual development and other functions in both sexes by responding to hormones like testosterone. The AR gene is responsible for producing the androgen receptor protein, a key player in how the body responds to androgens, a class of hormones including testosterone.
AR is located on the long (q) arm of chromosome X, at band Xq12. Arm ratio per GRCh38 - banding schematic.
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Overview
The AR gene (androgen receptor) encodes a protein that acts as a receptor for male sex hormones, known as androgens. These hormones are essential for the formation of male sexual traits and play broader roles in other bodily functions.
The androgen receptor is found in many tissues throughout the body, where it binds to androgens. This binding enables the receptor to regulate the activity of specific genes, influencing various biological processes.
What the gene does
The androgen receptor protein encoded by the AR gene enables cells to respond to androgens such as testosterone. Once an androgen binds to the receptor, the resulting complex travels into the cell's nucleus, where it attaches to specific DNA sequences. This binding action regulates the expression of certain genes, effectively turning them on or off as needed.
This gene regulation is critical for the development of male sexual characteristics during foetal development and puberty. Beyond its role in sexual development, the androgen receptor also contributes to other physiological processes in both males and females, including hair growth patterns and libido. The AR gene contains a region with a CAG trinucleotide repeat, which can vary in length among individuals.
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Chromosome location
The AR gene is located on the long (q) arm of the X chromosome at position 12, specifically at Xq12. This chromosomal location indicates that the AR gene follows an X-linked inheritance pattern.
Protein structure
The androgen receptor protein is composed of 920 amino acids and features several functional domains. Regions at amino acids 1-587 and 552-919 are involved in interactions with other proteins, specifically ZNF318 and LPXN, respectively. Modulating regions are found between amino acids 1-559, and disordered regions occur at 36-167 and 195-228. The protein contains a nuclear receptor (DNA binding) domain from amino acids 560-632, which includes two NR C4-type (Zinc finger) domains at 560-580 and 596-620. Further interaction sites include HIPK3 (572-662), CCAR1 (592-919), and KAT7 (625-919). A significant NR LBD (Domain) for ligand binding is located from amino acids 669-900.
Key variants
Variants within the AR gene can alter the function of the androgen receptor protein, affecting its ability to bind to androgens or regulate gene expression. These genetic changes can range from single base-pair substitutions to larger insertions or deletions. Certain variants involve an expansion of the CAG trinucleotide repeat segment within the gene.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1443C>A | p.Tyr481Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Androgen resistance syndrome |
c.1531A>T | p.Arg511Ter | Pathogenic | ★★☆☆ | AR-related disorder |
c.1605del | p.Pro534_Tyr535insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Androgen resistance syndrome |
c.1729T>C | p.Cys577Arg | Pathogenic/Likely pathogenic | ★★☆☆ | AR-related disorders |
c.1A>T | p.Met1Leu | Pathogenic | ★★☆☆ | Kennedy disease |
c.2063C>T | p.Ala688Val | Pathogenic/Likely pathogenic | ★★☆☆ | Kennedy disease |
c.2197G>A | p.Asp733Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Kennedy disease |
c.2270A>G | p.Asn757Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Androgen resistance syndrome |
c.2407dup | p.Gln803fs | Pathogenic | ★★☆☆ | AR-related disorder |
c.2494C>T | p.Arg832Ter | Pathogenic | ★★☆☆ | AR-related disorders |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the AR gene are associated with several inherited conditions, primarily impacting sexual development and neurological function. These include androgen insensitivity syndrome, which encompasses both Complete androgen insensitivity (CAIS) and Partial androgen insensitivity (PAIS), affecting how the body responds to androgens. Additionally, variants can cause Kennedy disease (SBMA), a neurodegenerative disorder. Some AR gene variants are also linked to an increased risk of Alopecia (male-pattern) and may play a role in other complex conditions.
- Alopecia (male-pattern)
- Androgen insensitivity syndrome (complete)
- Kennedy disease (SBMA)
- Partial androgen insensitivity (PAIS)
- Complete androgen insensitivity (CAIS) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic AR variants typically follow X-linked inheritance.
Carrier frequency by population How common is heterozygous AR carrier status across ancestry groups?UK clinical status
The AR gene is included on several NHS Genomic Medicine Service panels, indicating its clinical significance within the UK. It is listed as 'green' on the DDG2P panel, as well as on the Differences in sex development (R146) and Foetal anomalies (R21) panels, signifying that variants in this gene are considered to have a strong evidence base for pathogenicity.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the AR gene do?
The AR gene provides instructions for making the androgen receptor protein. This protein allows the body to respond to androgen hormones, which are crucial for male sexual development and other functions like hair growth and libido in both males and females.
What is androgen insensitivity syndrome?
Androgen insensitivity syndrome is a condition caused by variants in the AR gene. It affects how the body responds to androgens, leading to differences in sexual development that can range from partial to complete insensitivity to these hormones.
Can AR gene variants affect hair growth?
Yes, variants in the AR gene are associated with an increased risk of androgenetic alopecia, which is a common form of hair loss often referred to as male pattern baldness or female pattern hair loss. This suggests a role for the androgen receptor in regulating hair growth.
References
- Gottlieb B, Beitel LK, Nadarajah A. The androgen receptor gene mutations database: 2012 update. Human mutation. 2012. PMID: 22334387
- Zajac JD, Fui MN. Kennedy's disease: clinical significance of tandem repeats in the androgen receptor. Advances in experimental medicine and biology. 2012. PMID: 23560310
- Bennett NC, Gardiner RA, Hooper JD. Molecular cell biology of androgen receptor signalling. The international journal of biochemistry & cell biology. 2010. PMID: 19931639
- Adachi H, Katsuno M, Minamiyama M. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain : a journal of neurology. 2005. PMID: 15659427
- Beitel LK, Scanlon T, Gottlieb B. Progress in Spinobulbar muscular atrophy research: insights into neuronal dysfunction caused by the polyglutamine-expanded androgen receptor. Neurotoxicity research. 2005. PMID: 15897156
- Hillmer AM, Hanneken S, Ritzmann S. Genetic variation in the human androgen receptor gene is the major determinant of common early-onset androgenetic alopecia. American journal of human genetics. 2005. PMID: 15902657
- Levy-Nissenbaum E, Bar-Natan M, Frydman M. Confirmation of the association between male pattern baldness and the androgen receptor gene. European journal of dermatology : EJD. 2005. PMID: 16172040
- Poletti A, Negri-Cesi P, Martini L. Reflections on the diseases linked to mutations of the androgen receptor. Endocrine. 2005. PMID: 16388114
- Katsuno M, Adachi H, Tanaka F. Spinal and bulbar muscular atrophy: ligand-dependent pathogenesis and therapeutic perspectives. Journal of molecular medicine (Berlin, Germany). 2004. PMID: 15133611
- Gottlieb B, Beitel LK, Wu J. Nuclear receptors and disease: androgen receptor. Essays in biochemistry. 2004. PMID: 15242343