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AR
androgen receptor
The AR gene provides instructions for the androgen receptor protein, which plays a critical role in male sexual development and other bodily functions by responding to androgen hormones. The AR gene is responsible for producing the androgen receptor protein, which is essential for mediating the effects of androgen hormones, such as 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, or androgen receptor gene, encodes a protein that acts as a receptor for androgen hormones. Androgens are a group of steroid hormones that are crucial for the development and maintenance of male secondary sexual characteristics. They also play important roles in other biological processes in both sexes, including hair growth and libido.
The androgen receptor allows cells to respond to these hormones, initiating pathways that regulate gene expression. Variations in the AR gene can therefore lead to a spectrum of conditions affecting sexual development and other systems.
What the gene does
The androgen receptor protein, encoded by the AR gene, functions as a hormone-activated transcription factor. This means it binds to androgen hormones like testosterone and dihydrotestosterone (DHT), and this binding event triggers a cascade of molecular events. Once bound to an androgen, the receptor complex translocates to the cell nucleus where it binds directly to specific DNA sequences. This binding regulates the transcription of target genes, either activating or repressing their expression.
This regulatory action is fundamental for proper male sexual development, from foetal stages through to puberty. Beyond its role in sexual differentiation, the AR protein also influences other bodily functions, including bone density, muscle mass, and hair growth, in both males and females. The receptor's ability to modulate gene activity is critical for its diverse physiological roles.
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Chromosome location
The AR gene is situated on the long arm of the X chromosome, specifically at position Xq12. This chromosomal location means that it follows an X-linked inheritance pattern. Given its position, conditions associated with variants in the AR gene typically affect males more severely due to their single X chromosome.
Protein structure
The AR protein consists of 920 amino acids and features several distinct functional regions and domains. The N-terminal region, spanning amino acids 1-587, interacts with ZNF318. Within this region, amino acids 1-559 form a modulating region, and there are two notable disordered regions: one from amino acids 36-167 and another from 195-228.
The central part of the protein includes a nuclear receptor (DNA binding) domain from amino acids 560-632, which contains two NR C4-type (Zinc finger) domains at 560-580 and 596-620. This DNA-binding region also interacts with HIPK3 (amino acids 572-662). The C-terminal portion, from amino acids 552-919, interacts with LPXN. Furthermore, the protein contains an NR LBD (ligand-binding domain) from amino acids 669-900, and interacts with CCAR1 (amino acids 592-919) and KAT7 (amino acids 625-919).
Key variants
Variants in the AR gene can impact the structure and function of the androgen receptor protein, leading to a range of health conditions. These genetic changes can include single DNA building block alterations or larger insertions and deletions within the gene. The specific effect of a variant often depends on its location within the gene and how it alters the protein's ability to bind androgens or regulate gene expression.
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 | ★★☆☆ | Kennedy disease |
c.1531A>T | p.Arg511Ter | Pathogenic | ★★☆☆ | AR-related disorder |
c.1605del | p.Pro534_Tyr535insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Androgen resistance syndrome |
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 | ★★☆☆ | Kennedy disease |
c.2407dup | p.Gln803fs | Pathogenic | ★★☆☆ | Kennedy disease |
c.2494C>T | p.Arg832Ter | Pathogenic | ★★☆☆ | Kennedy disease |
c.967G>T | p.Glu323Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Androgen resistance syndrome |
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 affecting sexual development and neurological function. These include Androgen insensitivity syndrome, which presents as Complete androgen insensitivity (CAIS) or Partial androgen insensitivity (PAIS), impacting how the body responds to androgens. The gene is also implicated in Kennedy disease (SBMA), a neurodegenerative condition affecting motor neurons. Furthermore, AR gene variants are linked to an increased risk of Alopecia (male-pattern) and have been studied in relation to Polycystic ovary syndrome and Prostate cancer.
- Alopecia (male-pattern)
- Androgen insensitivity syndrome (complete)
- Kennedy disease (SBMA)
- Complete androgen insensitivity (CAIS) Dedicated page coming soon
- Partial androgen insensitivity (PAIS) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic AR variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
The AR gene is included in several NHS Genomic Medicine Service national panels. It is part of the DDG2P panel, and relevant to the Differences in sex development (R146) and Foetal anomalies (R21) panels, indicating its importance in diagnosing specific conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the AR gene?
The AR gene provides instructions for creating the androgen receptor protein, which binds to androgen hormones like testosterone. This binding allows the body to respond to these hormones, influencing male sexual development and other functions in both sexes.
How does the AR gene relate to androgen insensitivity syndrome?
Variants in the AR gene can cause androgen insensitivity syndrome, a condition where the body cannot properly respond to androgens. This can lead to a spectrum of effects on sexual development, ranging from partial to complete insensitivity.
What is the inheritance pattern for conditions linked to the AR gene?
Conditions associated with the AR gene typically follow an X-linked inheritance pattern. This means that the gene is located on the X chromosome, and males, having only one X chromosome, are generally more affected by variants than females.
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