The androgen receptor (AR) protein regulates transcription of certain genes. Usually this depends upon a central DNA-binding domain that permits the binding of androgen–AR complexes to regulatory DNA sequences near or in a target gene. The AR also has a C-terminal ligand-binding domain and an Nterminal transcription modulatory domain. These N- and C-terminal domains interact directly, and with co-regulatory, non-receptor proteins, to exert precise control over a gene’s transcription rate. The precise roles of these proteins are active research areas. Severe X-linked AR gene (AR) mutations cause complete androgen insensitivity, mild ones impair virilization with or without infertility, and moderate ones yield a wide phenotypic spectrum sometimes among siblings. Different phenotype expressivity may reflect variability of ARinteractive proteins. Mutations occur throughout the AR but are concentrated in specific areas of the gene known as hot spots. A number of these mutations of somatic origin are associated with prostate cancer. N-terminal polyglutamine (polyGln) tract expansion reduces AR transactivation, and when there are more than 38 glutamine residues it causes spinobulbar muscular atrophy, a motor neuron disease, due to a gain of function. Variations in polyGln tract length have been associated as risk factors with prostate, breast, uterine, endometrial and colorectal cancer, as well as male infertility.

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