Mutations In The Gene That Encodes The Androgen Receptor

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Now imagine if a steroid hormone receptor in your body was not there or was not functional. Your hormones would continue to flow throughout your body, but when they arrived at the target cell, there would be no place on the cell surface for them to dock. If they don't dock with their receptor, the target cell cannot tell that the hormones are there and thus does not know that it needs to change which genes it is expressing and to change the levels of expression of some of the genes it is already using. In the case of sexual development, one of the key receptors is the androgen receptor gene (AR gene). It is encoded by a gene on the X chromosome, and loss-of-function alleles of the AR gene are referred to as AIS mutations. Because these mutations prevent the production of functional testosterone receptor, the phenotype of XY individ uals is the result of a pattern of gene expression that has not been altered by signals from testosterone. The result is a disorder known as androgen insensi-tivity syndrome (AIS), sometimes also known as testicular feminization (TFM). AIS is seen in approximately 1 in 20,000 live births.

In XY embryos with an AIS mutation, the indifferent gonads receive the TDF signal and develop as testes while the Mullerian ducts regress in the presence of MIF. However, the cells of this embryo cannot sense the testosterone that is running around the body looking for androgen receptors. Instead, the somatic cells respond to the normal, low level of estrogen secreted by the adrenal cortex of both sexes, and the embryo develops along a female pathway (Figure 21.5). Consequently, the child at birth appears as a perfectly normal female. However, her vagina ends in a blind duct. The AIS female has no cervix, uterus, or fallopian tubes. Instead of fallopian tubes, there are two fully developed but undescended testes producing testosterone. These females are externally normal throughout childhood, puberty, and adult development, with the exception of a scarcity of underarm and pubic hair. Obviously, they will neither menstruate nor be able to bear children.

Given that such women are often detected as children or teenage girls, this is a serious issue in terms of how much information should be provided

FIGURE 21.5 AIS syndrome. Individuals with a defective androgen receptor have an XY karyotype. Their gonads are undescended testes, and their sexual anatomy is female, except they have no ovaries, cervix, or uterus. The phenotype can be either complete or partial, with the latter resulting in some sexual ambiguity.

Sperm with Y chromosome containing TDF fertilizes egg with X containing defective AR.

Sperm with Y chromosome containing TDF fertilizes egg with X containing defective AR.

Testes make testosterone which is undetected by the defective AR receptor.

Low levels of estrogen from the adrenals signal female development.

during diagnosis and counseling, how it should be provided, and who should receive the information. Some girls were not told that they had the AIS mutation, even though their doctors and parents knew. In such cases, the news can some as a shock if discovered later as an adult. However, there can also be serious health repercussions to not knowing if you have an AIS mutation, so withholding such information can be dangerous.

As noted above, the AIS female also possesses a fully developed set of testes that are located internally above where the scrotum would normally be. These testes reside inside the body, existing at a higher temperature inside the body than would normally exist for testes that have descended into the scrotum. It is recommended that such a female have her testes removed as a young adult because of an increased risk of testicular cancer that can develop later in life as a result of the elevated temperature.

AIS females are often considered quite attractive by contemporary standards, and they are often taller than the average woman. The health implications of AIS are risk of testicular cancer, infertility, gonadectomy, hormone replacement therapy, and, eventually, osteoporosis. Psychologically, they are as stable and happy (or not) as women with two X chromosomes who end up coping with fertility issues. They can be expected to live perfectly happy, normal lives and, when they so choose, become parents of adopted children or stepchildren.

Do AIS women (with XY karyotype and no functional androgen receptor) have the same characteristics as TDF-negative women (with XY karyotype and no functional TDF protein)? No. Recall that the TDF-negative woman, in the absence of the TDF signal, has produced female gonads, which provide an estrogen-dominated hormonal environment. Although they are infertile because their meiotic processes needed two copies of the X chromosome, they have a full set of female anatomy. The AIS woman, with an active TDF signal, has male gonads, only as much estrogen as the adrenal glands can supply, and no ovaries or uterus. Thus a TDF woman would be harder to identify without genetic testing, and an AIS woman has cancer risk to deal with in addition to infertility.

So what we see from this step-by-step walk through of the first several steps in sex determination in humans is the requirement for at least four elements: a Y chromosomal signal; a sensing mechanism in the indifferent gonad to respond to the Y chromosomal signal; a hormonal signal produced by the gonads (androgens or estrogens); and a set of sensors, androgen, and estrogen receptors, in the somatic tissues responding to the secondary signal coming from the gonads. In fact, there are other genes involved in sex determination that can affect a variety of the secondary steps that taking place in different cell types and tissues in different portions of the anatomy as the primary and secondary somatic characteristics emerge.

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