AR gene

The AR gene (AR stands for: Androgen Receptor) is a protein-coding gene located on chromosome Xq12. Alternative splicing leads to several transcript variants that encode different isoforms.

The androgen receptor gene is more than 90 kb long and encodes a protein with three main functional regions: the N-terminal region, the DNA-binding region and the androgen-binding region. The protein acts as a steroid hormone-activated transcription factor. After binding of the hormone ligand, the receptor detaches from the accessory proteins, migrates into the nucleus, dimerizes and then stimulates the transcription of androgen-responsive genes.

The AR gene contains 2 polymorphic trinucleotide repeat segments encoding polyglutamine and polyglycine tracts in the N-terminal transactivation domain of its protein. The expansion of the polyglutamine tract from the normal 9-34 repeats to the pathogenic 38-62 repeats causes spinal bulbar muscular atrophy (SBMA, also known as Kennedy syndrome).

Depending on their localization, mutations in the AR gene can induce disorders at all levels of the androgen receptor mechanism, e.g. disorders in androgen binding, DNA binding or transactivation. With over 90% of all mutations, point mutations represent the largest group of androgen receptor gene defects. This results in an amino acid exchange in the receptor gene; splicing defects or non-sense mutations are rarer.

Androgen insensitivity: If, for example, there is a mutation in the androgen receptor in the male genotype (46, XY), this can lead to complete (CAIS) or partial androgen insensitivity (PAIS; OMIM 300068) (Mongan NP et al. 2015). The endocrinological parameters of these androgen receptor defects correspond in part to those of 5a-reductase deficiency. Due to the different phenotype, both the timing of the clinical abnormality and the "clinical picture" can vary significantly. Phenotypically male patients often first become conspicuous due to inadequate pubertal development or an unfulfilled desire to have children in the case of infertility. Women with complete androgen resistance are often first noticed due to primary amenorrhea. In the case of androgen resistance, for example, the molecular biological detection of "somatic mosaics" provides a conclusive explanation for the sometimes pronounced genotype-phenotype discrepancies (Wang H et al. 2019).

Mutations in the AR gene are also associated with bulbar muscular atrophy, X-linked.

Androgen receptors (ARs) (dihydrotestosterone receptors) are nuclear hormone receptors of the NR3C class, which also includes mineralocorticoid, progesterone and glucocorticoid receptors. ARs are expressed in bone marrow, mammary gland and prostate tissue. The specific (natural) ligands of the androgen receptor are the sex hormones testosterone and dihydrotestosterone. In humans, the androgen receptor is encoded by the AR gene, which is located on Xq11-12, i.e. on the long arm of the X chromosome. The AR is produced in most tissue types in humans. The different activities are due to a number of proteins that act as coactivators or corepressors of the receptor.

Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and influence cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins such as ZBTB7A, which recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, thereby negatively regulating androgen receptor signaling and androgen-induced cell proliferation (Cui J et al. 2011). Transcriptional activation is also downregulated by NR0B2.

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