ANÁLISE MOLECULAR DO GENE DO RECEPTOR DE ANDRÓGENOS EM HOMENS COM SUSPEITA DE INFERTILIDADE

Abstract

The androgen is a generic term usually applied to describe a group of sex steroid hormones. Androgens are produced primarily by a male's testes. However, some small amounts are also produced by the ovaries in females and by the adrenal gland, in both sexes. Androgens are responsible for the male sex differentiation during embryogenesis at the 6th or 7th week of gestation , triggering the development of the testes and penis in male fetuses and is directed by the testicular determining factor, the gene SRY (sex determining region on Y chromosome), located on the short arm of chromosome Y. The differentiation of male external genitalia in penis, scrotum and penile urethra occurs between the 9th and 13th weeks of pregnancy and requires adequate concentration of testosterone and converting this to another more potent androgen dihydrotestosterone (DHT), through the action of 5α reductase in target tissues. The actions of testosterone and DHT require the presence of functional androgen receptors, which, after the connection with these hormones, activate the transcription of specific genes in target tissues. The AR gene is a protein coding gene located at Xq11.2-q12. It spans over 90 kb and codes for a protein that functions as a steroid-hormone activated transcription factor. The AR, like other members of the nuclear receptor superfamily, has three major functional domains: the AR is characterized by a modular structure consisting of four functional domains: an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region, and a ligand (androgen-) binding domain (LBD). Mutations in the AR gene cause the X-linked Androgen Insensitivity Syndrome (AIS) characterized by androgen unresponsiveness, which affects the proper male sexual development both at embryogenesis and puberty. As a genetic disorder, AIS presents a problem and a burden to the affected people and their families and a major medical challenge for the health providers. This impaired response to androgen results from the incapacity or reduced capacity of the androgen receptor (AR) to transactivate androgen-responsive genes in target cells, and leads to abnormal differentiation and development of male internal and external genitalia, and thus leading to male pseudohermaphroditism.