Androgen Insensitivity Syndrome (AIS) a Sex-Linked Gene That Helps to Determine Sex

Androgen Insensitivity Syndrome (AIS) — A Sex-Linked Gene that Helps to Determine Sex

Our genes, our genetic make-up, is/are not independent of the rest of our bodies, but rather, are closely integrated in and with all of our body processes. Androgen Insensitivity Syndrome (AIS) may be used to illustrate how a person’s genetic make-up, hormones, biochemistry, embryonic development, and phenotype are all closely tied together and integrated, and may serve as a good example of how our “sex” is also a phenotype that is under genetic control.

Hormones are chemical “messengers” which are made in specific organs in our bodies, called endocrine glands. These hormones travel, via the blood, to other areas of the body where they exert chemical control over some process that is occurring in that location. For example, the hormone insulin is made by the pancreas and travels to the liver, where it “tells” the liver to take sugar out of the blood and store it up by making glycogen. For many of our hormones, reception of their message is dependent upon proper functioning of other chemicals in the cells of the target organs. For example, in type II diabetes, the person’s body is making adequate insulin, but the insulin receptors in his/her liver are not functioning properly, so the liver never gets the message to store up sugar, and the person’s blood sugar level goes too high.

Androgens, including testosterone, are hormones which all of us, both men and women, make in our bodies. In both men and women, testosterone is responsible for the coarse pubic and axillary (armpit) hair which starts to grow at puberty. Since the testes are the primary organs which produce testosterone, people with testes typically have a higher level of testosterone in their bodies than people without testes, and that is responsible for development of most of the traits that we consider “male”. As in the above example, the testosterone produced by the testes is secreted into the blood and travels to many other areas of the person’s body to exert its effects, and also as above, testosterone (androgen) receptors are required in those target locations. By the way, all of us, both men and women, also make at least some estrogen, and for all of us, both men and women, how we look – our phenotype – is typically influenced by the effects of both the testosterone and estrogen in our bodies.

Testosterone exerts its effect in a somewhat indirect fashion. When testosterone reaches a target organ or target tissue, it must be absorbed into the cells of that tissue. Inside those cells is a kind of protein, coded for by the person’s DNA, called an androgen receptor which, as its name implies, receives the testosterone and binds on to it. As the testosterone binds onto the androgen receptor protein, it causes a change in that protein’s native conformation which converts the inactive receptor into an active DNA-binding state, thereby enabling the protein to chemically interact with that cell’s DNA. Thus, once testosterone has attached to the androgen receptor, that pair goes into the nucleus of the cell and interacts with the person’s DNA, thereby controlling transcription of other genes. Many of those genes control “male” traits such as embryonic development of male external genitalia.

All human embryos, whether XX or XY, develop identically for the first 6 weeks of life, all have undifferentiated external genitalia, and all have rudimentary primordial gonadal tissue that can, potentially, form either male or female organs. If the embryo baby has a Y chromosome, that Y chromosome contains a gene which codes for the formation of testes from the primordial gonadal tissue at about 6 weeks. Testes, by the way, form in approximately the same location in the abdomen as ovaries do, with the difference that while ovaries “stay put,” normally, testes later move down lower in the abdomen and eventually, out the bottom of the abdomen and into the scrotum (thus, we say they “descend”). Formation of the testes is not dependent on androgens such as testosterone, but rather, once testes have begun to form, they start to secrete androgens, including testosterone, as well as another hormone called anti-Müllerian hormone. The anti-Müllerian hormone has an inhibitory effect which causes regression of the primordial female system, thus inhibiting the development of Fallopian tubes, uterus, and the upper portion of the vagina. The androgens, including testosterone, have a stimulatory effect on development of the male system, which causes development of the epididymis, vasa deferentia, and seminal vesicles during about the 9th through 13th weeks. In the absence of the effects of these hormones, development of the male system does not occur and instead, by “default,” the female external genitalia (labia, vagina) develop.

However, in order for embryonic development of the male organs to take place, the androgen receptor protein has to be functioning properly. As just mentioned, in type II (adult onset) diabetes, the person’s body is making enough insulin, but the insulin receptors in that person’s liver cannot properly receive the insulin. Similarly, the androgen receptors must be functioning properly to receive testosterone. Since the androgen receptor molecules are a kind of protein, that means they’re under the control of the gene that codes for them, and any mutation of that gene – totally missing androgen receptor gene, missing chunk of gene, frameshift mutation, etc. – can cause the protein to be absent or have an abnormal native conformation that is incapable of binding on to testosterone. Thus, even though lots of testosterone is present, the androgen receptor can’t bind on to it, and therefore is unable to control transcription of other genes. This would make that person’s organs/tissues appear to be totally resistant or insensitive to the effects of testosterone, hence the name “Androgen Insensitivity Syndrome.”

Now, consider the effect that would have on the embryonic development of an XY individual. Since the Y chromosome is present, that person has the gene to make testes, so the testes begin to develop and start to secrete testosterone and anti-Müllerian hormone. Since the anti-Müllerian hormone is functioning properly, development of the uterus, Fallopian tubes, and the top end of the vagina will be inhibited. However, despite lots of testosterone, the rest of the body never gets the message, so the epididymis, vasa deferentia, and seminal vesicles will not develop. Also, without the effects of testosterone, external male genitalia (scrotum, penis) will not form, but rather by “default,” as is normally the case in the absence of the influence of testosterone, the external genitalia will be totally female, including the labia and most of the vagina. Thus, even though this person is chromosomally XY and has testes, she is phenotypically female. Actually, since a girl/woman with AIS is totally resistant to the effects of testosterone, it’s kind-of like she’s more female than a “typical” XX female whose phenotype is influenced by the testosterone in her body. Usually her testes do not descend, but remain in her abdomen, and thus, as with any undescended testes, they are more likely to develop testicular cancer. When this baby is born, to her doctors, nurses, and parents she looks like any other normal little girl, but her undescended testes may be discovered later if they are in such a position as to give the appearance of a hernia.

What about later in life? In some girls with AIS, their undescended testes are never apparent, and the condition is discovered when they fail to begin menstruating despite normal body development at puberty. Even XY men produce some estrogen in their bodies. In the bodies of women with AIS, some of the testosterone they produce is converted to estrogen, and that, coupled with the estrogen being produced by their bodies is enough that their estrogen levels are about the same as an XX woman in the “follicular” phase of her monthly cycle, and women with AIS go through normal development at puberty (breast development, widening of the hips, etc.). Actually, since the effects of estrogen are unopposed by testosterone in their bodies, breast development is often more significant than XX women whose development is also influenced by testosterone. Since testosterone plays a role in teenage acne, women with AIS typically have very clear, acne-free complexions. Since the testes do produce some estrogen, and since some of the testosterone they produce is converted to estrogen, their presence in her body can aid in development at puberty, but due to the increased risk of testicular cancer in undescended testes, physicians often encourage their removal soon thereafter. Since she doesn’t have a uterus or ovaries, a woman with AIS will not menstruate and will not be able to become pregnant, thus may want to consider adopting children. Since, as mentioned above, growth of axillary and pubic hair is controlled by testosterone, women with AIS will usually not have that type of coarse hair, which can be very upsetting to a teen being ridiculed by her classmates during gym class showers. Depending on the shortness of the woman’s vagina, once she is sexually active, that may help to stretch it, but in some cases, a doctor might advise surgery to lengthen it.

While a girl who has AIS has enough estrogen in her body to stimulate normal (or greater than normal) breast development, size-wise, she lacks the hormones needed to stimulate development of the actual mammary gland tissue. If, however, she is given supplemental hormones during puberty, mammary gland tissue will properly develop, and as an adult, she will be as capable as any other adoptive mother of nursing a baby.

The genetics of AIS is an intriguing part of this story. As mentioned above, AIS may be attributed to a mutation in the gene that codes for the androgen receptor protein. Thus, AIS is, essentially, an allele that influences the sex of the individual, but interestingly, AIS is also an X-linked, recessive allele. In other words, testosterone sensitivity is coded for by a gene on the X chromosome (and the recessive allele codes for a non-functioning receptor). If we let XA represent the allele that codes for functional androgen receptor and Xa represent the allele that codes for non-functional androgen receptor, then a person who is XAXA would be a female who is normally receptive to testosterone. Someone who is XAXa would be a carrier female, and because this is an X- linked gene, her body would be a mosaic of tissue types – some of her cells would be sensitive to testosterone while others would be resistant, depending on which X chromosome was active and which had become a Barr body. Some women who are heterozygous have delayed menarche (onset of menstruation) or may have reduced or asymmetrical development of pubic or axillary hair. Someone who is XAY would be a male who is normally receptive to testosterone. However, unlike other sex-linked alleles, because AIS affects the sex of the person, someone who is XaY would be a female with AIS. If a carrier woman and a man get married, the Punnett square for their children would look like:

Thus, ¾ of their children would be expected to be girls and only ¼ boys. Of the girls, we would expect 33% to have normal testosterone receptors, 33% to be carriers, and 33% to have AIS (of all the children, that would be ¼ each).

When we discussed other sex-linked genes such as hemophilia, red-green colorblindness, and white-eyed fruit flies, we took things one step farther, and showed how a carrier female (XX') and affected male (X'Y) could produce a homozygous recessive female (X'X') offspring. Because AIS affects the sex of the individual, that genetic cross wouldn’t be possible. First of all, someone who is X'Y would be female, not male, and so most likely would get married to a man (XY), not another woman (XX'). Secondly, since she doesn’t have a uterus, she can’t get pregnant. Thirdly, between the fact that her testes, if not surgically removed, are undescended (and therefore sterile) and the fact that her testes, along with the rest of her body, are insensitive to the effects of testosterone (and therefore sterile), they would produce no sperm (and anyway, sperm would have no way out). Unlike other X-linked alleles, a girl would not inherit this from her father. An X'X' individual would be extremely rare because no one could inherit that combination, so the only way to get that would be in the extremely unlikely event that mutations suddenly occurred in the X chromosomes that both parents gave to that daughter.

Several famous actresses and female athletes have AIS. Actually, the idea of a successful female athlete with AIS is of interest because it is generally thought that athletic prowess is related to testosterone, yet here is a woman whose body is totally unaffected by testosterone. Because athletic organizations, including the Olympics, have not understood that, these women have, at times, been unfairly barred from competition, based solely on the fact that they have a Y chromosome, and they have been forced to bring law suits to be permitted to compete. Because of our society’s overall lack of understanding and acceptance, some doctors try to convince parents of an androgen-insensitive daughter to keep that a secret from her, but that never works. Sooner or later, she will find out or figure it out, somehow, often accompanied by feelings of guilt, embarrassment, and bewilderment, so wouldn’t it be much better to hear it gradually from loving, supportive parents as she grows up than to, as a young adult, suddenly hear it from someone else?

Some things to discuss with your study group: what would you do if...?

• What if one of your neighbors or another student here at school told you that his/her daughter has AIS? What would you think? What would go through your mind when you met that girl for the first time? What would you say to your own children about her?
• Suppose you are the parent of a cute little girl (pick an age: 2? 4? 8?) who loves dressing up in frilly dresses and playing with baby dolls and who, you were told, had a hernia that would have to be surgically corrected. What if the doctor came out of surgery to tell you your little girl did not have a hernia, but they had just discovered she had testes? What if the doctor, then, recommended getting a karyotype done, and the results came back saying that chromosomally, she’s XY? How would you feel? What would go through your mind?
• What would you say to her as she was growing up? What would you say to her when she told you she was going to be a mommy and have babies when she grows up? What would you say to her before or while she was taking junior high health class? What would you say to her when she didn’t start menstruating like all her peers, so they were making fun of her? What would you say to her when she didn’t want to go to junior-high gym class because, during the mandatory group showers afterwards, the other girls ridiculed her because she lacked pubic hair? What would you say to her when she was going through all the insecurities and self-doubts that teenagers go through?
• One for the men: suppose you started dating a woman, fell deeply in love with her, and the two of you were thinking about getting married. What if, in the course of a conversation one day, she told you that she had AIS, that her karyotype was XY, and that she was scheduled to have surgery next week to remove her undescended testes? What would you think? What would you say to her? What would you do?
• One for the women: there is an analogous condition in which a person can be XX, yet due to influence, or lack thereof, of the sex hormones, be phenotypically male. I recall reading a medical case history where a couple was not having success conceiving a child, and so they were undergoing medical testing to determine the cause. In the course of the testing, it was discovered that the man was XX. How do you think you would react if that was your husband?