Androgen insensitivity syndrome - AR gene

The androgen insensitivity syndrome (AIS) is a congenital disorder that affects sexual development before birth and during puberty. From 7 to 8 weeks of gestation the fetuses begin to develop their reproductive system. In the XY karyotype it is necessary the intervention of male hormones -testosterone and 5α-dihydrotestosterone (androgens)- to initiate the secondary process of sexual differentiation and to develop a complete male reproductive system. In the AIS there is an interruption in the development of the reproductive system of the fetus, because the insensitivity to androgens, causes the development of external genitalia following the female line, while the development of internal organs is previously stopped by the MIF (Mullerian Inhibitor Factor), a hormone produced by the fetal gonads. In this way, those affected with IAS usually manifest a female phenotype, but with absence of female internal organs, pubic hair and menstruation.

There are two differentiated forms of IAS, the complete form (CASI: Complete Androgen Insensitivity Syndrome or Morris Syndrome), where the tissues are completely insensitive to androgens, and the incomplete form (PAIS: Partial Androgen Insensitivity Syndrome or Reifenstein's syndrome), where the tissues are insensitive at different degrees. Individuals with the complete form of androgen insensitivity have female external genitalia, usually with small labial folds, short vagina with blind termination, absence of structures derived from the Wolff duct and prostate, along with gynecomastia. This form has a uterus, ovaries and fallopian tubes. In addition, people with complete androgen insensitivity syndrome also have sparse or absent hair in the pubic area and armpits.

In the PAIS form, on the other hand, the appearance of the genitals can vary from totally female to totally male, passing through intermediate degrees of male/female ambiguity. The predominant phenotype is female, in this case, with female external genitalia, with possible presence of pubic hair, possible clitoromegaly and partial or complete labial fusion. In other cases, the phenotype is masculine, called Reifenstein syndrome, and includes micropenis, perineal hypospadias and cryptorchidism. Other individuals, considered the milder (MAIS: Mildest Androgen Insensitivity) have a normal male phenotype, including internal and external genitalia, but during puberty may have breast enlargement, poor facial and body hair and micropenis, in addition to having altered the sperm production (oligozoospermia or azoospermia).

The various forms of IAS are due to mutations in the AR (androgen receptor) gene, located on the long arm of the X chromosome (Xq12). This gene encodes a protein called androgen receptor (AR). Androgen receptors allow cells to respond to androgens to direct male sexual development before birth and during puberty. Androgens and androgen receptors also have other important functions, both in males and females, such as the regulation of hair growth and sexual desire.

More than 600 different mutations in the AR gene have been identified in people with androgen insensitivity syndrome. Most of these mutations are changes of base pairs. Other mutations insert or delete multiple base pairs in the gene or affect how the gene encodes a protein. Some mutations give rise to an abnormally short version of the androgen receptor protein, while others result in the encoding of an abnormal receptor that cannot bind to androgens or DNA. As a result, cells that are sensitive to androgens become less sensitive to these hormones or cannot synthesize these hormones. Affected individuals are genetically male, with one X chromosome and one Y chromosome in each cell. However, because your body is unable to respond to androgens, they may have female sexual characteristics or signs of male and female sexual development. Mutations that completely eliminate receptor function give rise to the syndrome of complete androgen insensitivity. Genetic changes that significantly reduce but do not eliminate the activity of the androgen receptor cause the partial insensitivity syndrome. The mild form is due to genetic changes that only slightly reduce the activity of the receptor.

The androgen insensitivity syndrome (AIS) is inherited with a recessive pattern linked to the X chromosome. In males, an altered copy of the gene in each cell is sufficient to cause the disease. In women, a mutation in both copies of the gene would have to happen to cause the alteration. Because women are unlikely to have two altered copies of this gene, men are affected by X-linked recessive disorders much more frequently than women. A characteristic of inheritance linked to the X chromosome is that parents cannot transmit traits linked to the X chromosome to their children. About two-thirds of all cases of androgen insensitivity syndrome are inherited from mothers carrying an altered copy of the AR gene on one of their two X chromosomes. The remaining cases are due to a new mutation that can occur in the ovule of the mother before giving birth or at the beginning of fetal development.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with Androgen insensitivity syndrome, by means of the complete PCR amplification of the exons of the AR gens, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).