gene located on the X chromosome at Xq11–12. Deficiencies At least 165 disease-causing mutations in this gene have been discovered. The androgen insensitivity syndrome, formerly known as testicular feminization, is caused by a mutation in the androgen receptor gene on the X chromosome (locus: Xq11–Xq12). The androgen receptor seems to affect neuron physiology and is defective in Kennedy's disease. In addition, point mutations and trinucleotide repeat polymorphisms have been linked to a number of additional disorders. CAG repeats The AR gene contains CAG repeats that affect receptor function, where fewer repeats leads to increased receptor sensitivity to circulating androgens and more repeats leads to decreased receptor sensitivity. Studies have shown that racial variation in CAG repeats exists, with African-Americans having fewer repeats than non-Hispanic white Americans. The racial trends in CAG repeats parallels the incidence and mortality of prostate cancer in these groups. Mutations The enhancer and the gene encoding for these receptors contain recurrent mutations, such as structural rearrangements and copy number changes, acquired in the progression of metastatic castration-resistant prostate cancer (mCRPC) treatment with therapy targeting these receptors (abiraterone, enzalutamide), make the disease progression determined by the androgen receptor genotype. Structure Isoforms Two isoforms of the androgen receptor (A and B) have been identified: AR-A – 87 kDa; N-terminus truncated (lacks the first 187 amino acids), which results from in vitro proteolysis. AR-B – 110 kDa; full length Domains Like other nuclear receptors, the androgen receptor is modular in structure and is composed of the following functional domains labeled A through F: A/B) – N-terminal regulatory domain contains: activation function 1 (AF-1) between residues 101 and 370 required for full ligand-activated transcriptional activity activation function 5 (AF-5) between residues 360–485 is responsible for the constitutive activity (activity without bound ligand) dimerization surface involving residues 1–36 (containing the FXXLF motif; where F = phenylalanine, L = leucine, and X = any amino acid residue) and 370–494, both of which interact with the ligand binding domain (LBD) in an intramolecular head-to-tail interaction C) – DNA binding domain (DBD) D) – Hinge region; flexible region that connects the DBD with the LBD; along with the DBD, contains a ligand dependent nuclear localization signal E) – Ligand binding domain (LBD) containing activation function 2 (AF-2), responsible for agonist induced activity (activity in the presence of bound agonist) AF-2 binds either the N-terminal FXXFL motif intramolecularly or coactivator proteins (containing the LXXLL or