Male Gender Identity in an Individual With Complete Androgen Insensitivity Syndrome, Part 1 – DNA, Genes and the Androgen Receptor

When I first saw this recent publication, Male Gender Identity in Complete Androgen Insensitivity, I thought, “Hey, this case has really interesting ramifications about gender identity.  I’ll make a blog post about it!”

Then, I broadcast on my blog that I was going to make a post about it.  Big mistake.

As I drilled deeper and deeper into the literature and went down different tracks and tangents, I realized that I had potentially bitten off more than I could chew.

This subject, if explained correctly (my own anal definition of “correctly”) would touch on aspects of molecular biology, genetics, biochemistry, cell biology, physiology, embryology, psychology, sociology, behaviorology, and probably other “ologies” I can’t even think of.

But not being one to give up so easily on something (especially in public), I forged ahead.  In doing so, I realized that in order to explain this subject in a way that would have everyone on the same page, I would need to bring in some very basic information about how genes work and how proteins are made.  Why?  Because Complete Androgen Insensitivity Syndrome (CAIS) is due to genetic mutations of the androgen receptor (AR), and the AR is a transcription factor in that, when androgens such as testosterone bind to it, it sits down on DNA and turns on genes.

Now all this talk about explaining DNA and genes and stuff like that always gets me thinking about one thing above all others:

O.J. Simpson.

That’s right, Orenthal James Simpson, “The Juice,” former star running back for the Buffalo Bills, NFL hall-of-fame inductee, actor and convicted felon, currently serving 15 years in Nevada for armed robbery and kidnapping.

What is the connection between O.J. and DNA?  You might remember a case in Los Angeles in 1994 involving Mr. Simpson as the main suspect in the murder of his ex-wife, Nicole Brown, and her friend, Ron Goldman.  His televised murder trial lasted nine months.

At the time of the O.J. Simpson murder trial in 1995, I was doing postdoctoral research in a lab at a university out west.  My lab mates and I watched the trial when we could, especially the testimony regarding the DNA evidence against Simpson.

The DNA evidence came from blood samples taken where the bodies were found, from bloody gloves, one found at the scene of the crime and the other found at Simpson’s estate, and from bloody footprints at the scene of the crime, all containing DNA from Brown, Goldman and Simpson.  The technology for DNA fingerprinting was relatively new at the time, and the prosecution took great pains to explain it to the jury.  The problem was, the pains they took actually became painful to watch.

I remember that guy drawing DNA double-bonds, DNA base pairs, A, T, C, G, and droning on about how the DNA analysis was done and how DNA works and what DNA is made of and blah blah blah…  He was so boring and so uninspiring and didn’t explain it all in lay-terms for the jury (I thought anyway) and I could only think, “Man, you are losing your audience!!”

In the end, after nine months of testimony and acrimony and courtroom theatrics and Johnnie Cochran’s catchy rhymes and Judge Ito’s inability to keep the court in order, and blatant mistakes by the people investigating the crime (one police scientist-in-training carried a vial of blood from the crime scene in her lab coat pocket for a day before submitting it as evidence) and the prosecution (asking O.J. to try on the bloody glove), plus ineffective explanations about the DNA evidence, the jury only needed four hours to deliberate to an acquittal.

So much of the case hung on that DNA evidence that botching it and its explanation, in my opinion, sunk the prosecution’s case.

At the time of the O.J. Simpson trial, I was part of a mixed bunch of scientists in the lab I was telling you about.  There were protein biochemists, biologists (like me) and molecular biologists (the folks to play with DNA and engineer genes).  A few weeks after the verdict, one of my fellow biologists, who I’ll call Kevin, was asking one of the molecular biologists, who I’ll call Artie, to explain a new DNA engineering technique.

Artie grabbed a scratch piece of paper and started enthusiastically drawing genes and sequences and DNA cuts and splices, talking a mile a minute.  Kevin listened patiently for about 30 seconds to Artie’s very animated explanation and then politely stopped him by saying,

“Dude, O.J. is walkin’ …”

What am I getting at?  Unlike what happened in the O.J. Simpson trial, I want to avoid unintelligible explanations about DNA and how genes work that would result in the acquittal-level confusion of my audience.

Now for all this explaining, I say, “Thank goodness for YouTube!”  More on that in a little bit.

The Androgen Receptor (AR)

The AR gene, located on the X-chromosome at location Xq11-12, is one of the most mutated genes in the human genome.  So much so that there is a database just for AR mutations.  At the writing of this post, there are almost 400 known mutations of the AR gene.  That’s alot!

Because the AR gene is on the X-chromosome, individuals with XY chromosomes (usually being natal males) carry only one copy of the gene, that which came from their mother.  If that copy of the gene happens to be mutated, then a phenotype (a physical manifestation of the mutation) may be more readily noticable.

In XX individuals (usually natal females), one mutated copy of the gene inherited from one parent can be masked by a wild-type (i.e. normal) copy of the gene inherited from the other parent.  In that way, XX individuals can unknowingly be carriers of a mutated AR gene that could show up with a phenotype in their XY offspring.

The structure of the AR gene and protein are shown in the diagram below:

From Rajender et al., 2007; Figure 1

The location of the AR gene on the X-chromosome is depicted in the top part of the diagram.  The structure of the AR gene is shown in the middle, with the boxes depicting its 9 exons and the lines between the boxes depicting introns.  When the DNA of genes are transcribed into RNA, the exons are the sequences that encode the mature protein (i.e. the product of the gene) whereas introns are spliced out.  (I’ll provide better information about all this below.)

As I mentioned before, the AR is not only a receptor — it’s also a transcription factor, as are all steroid hormone receptors.  When the ligand (an androgen such as testosterone or dihydrotestosterone) binds to the AR, it brings about a conformational change that allows other proteins to bind to the AR to form a complex.  The complex becomes a functional unit that can sit down on a specific DNA sequence in different genes and initiate transcription (i.e. turn the genes ‘on’).

In order to do all those things, the AR protein has a number of specialized domains which are depicted the figure provided above.

The N-terminal domain (i.e. the front end of the protein) has sequences that encode a transactivation domain that helps the AR turn on genes, plus a coregulator binding domain that allows the AR to bind to other proteins.  (See on the AR database all of the known  proteins that interact with the AR.)

In the center of the protein there is another coregulator binding domain plus a DNA-binding domain that allows the AR to bind to specific sequences in the DNA of certain genes.  At the C-terminal end of the AR (i.e. the back end of the protein), there is a domain that binds the ligands, which are androgens such as testosterone and dihydrotestosterone (DHT).  There is also a sequence of amino acids for nuclear localization that helps the AR become transported from the cell cytoplasm, where it is made, into the cell nucleus where it does it’s work.

Now the AR is not a flat candy bar of a protein like that depicted in the diagram above.  The amino acid sequences of the different domains of the protein fold into very specific 3-dimensional configurations that allow the AR to function properly.

So, a mutation in the DNA-binding domain would not allow the AR to sit down on DNA, a mutation in the ligand-binding domain would not allow it to bind testosterone or DHT, and a mutation in the coregulator binding domains would not allow the AR to bind to coregulator proteins and turn on genes.


Clear as mud, right?  Well, that’s where YouTube comes in.

Here is video about DNA structure:

Here is a great PBS video that explains how DNA makes proteins, from transcription to translation.  (The sound effects crack me up.)  In this  first part of this video, the AR and its coregulators would be the colored group of proteins that grabs the DNA chain to start the transcription.

Here is a video that describes how mutations can arise in DNA gene sequences and how two different types of mutations affect the protein gene product:

Sorry for all the homework.  I hope you enjoy the videos and can understand what I’ve talked about so far regarding the androgen receptor, it’s gene and it’s protein structure.  If you have any questions, please ask in the comments.

In Part 2 of this series, I’ll talk about the different AR gene mutations and their relationship with Androgen Insensitivity Syndrome, which was mentioned in a previous post with a link to an informative article.


Free reference for this post:
Rajender S, Singh L, Thangaraj K, 2007, Phenotypic heterogeneity of mutations in androgen receptor gene.  Asian J Androl 9:147-179.

This entry was posted in Science/Biology and tagged , , , , , . Bookmark the permalink.

18 Responses to Male Gender Identity in an Individual With Complete Androgen Insensitivity Syndrome, Part 1 – DNA, Genes and the Androgen Receptor

  1. Josh says:

    Information overload. My head is about to explode, lol.

    • Yeah, I had one person say that some of what I wrote was “completely incomprehensible.” Guess I didn’t make my goal of writing in a way that everyone can understand.

  2. sara nichols says:

    I thought this was very informative.

  3. Julie says:


    I am a crime fiction writer and I am always looking for those iteresting plot twists –althought with OJ, truth was definitely stranger than fiction.

    Here’s my question, which is what brought me to this site (very nice, very informative, btw):

    Can DNA evidence (think crime scene) show the suspect as male, yet from all outward appearances the suspect is female, and can the reason for that be that the person has AIS? What is the difference between AIS and Chimerism?

    Thanks for your help.


    • Thank you for your nice comments about my blog, Julie.

      To answer your questions, yes, DNA could show male XY chromosomes from a person who is otherwise female. That can occur in cases of AIS and also other intersex conditions/disorders of sex development.

      Chimeras are people or animals that result from the joining of two zygotes. AIS is an intersex condition that arises from mutation of the androgen receptor, as explained in Parts 1-4 of my blog post on the topic.

      Having said that, I admitedly struggled with your questions, not the content per se but the reason behind them. I kept thinking of Jeffrey Eugenides and his novel Middlesex. Although he said in interviews that he contacted the ISNA while he was writing it and received almost universally positive feedback from the intersex community about his book after it was published, the criticisms I have heard were that he never interviewed even one intersex person while writing the book even though the book’s main character is intersex. In addition, he was criticized for passing himself off as an expert on intersex conditions while he is not, and he was criticized for not advocating for the intersex community even though he won a Pulitzer Prize by writing about a main character who is intersex.

      I am also sensitive to the “plot twist” concept as a trans person because some people who have perpetrated violence toward trans people use the excuse that they were “tricked” when the trans person’s assigned sex at birth became known to them. There are many people who take offense to us because we are seen as deceivers or because they feel that we have purposely done something to trick or fool them by not disclosing our birth sex.

      After giving it some thought, though, I wondered if I wasn’t being too sensitive. I have no information about your book (whether it be potential or in-progress), the characters, the plot or how it is being/will be written, so I have no idea whether it might be exploitative of intersex people. Because of that, I decided to go ahead and reply.

      I’m letting you know all of this as food for thought, and am also putting it out there for my readers, as some of them are intersex and many are transgender. They might like to weigh in on this topic.

  4. j says:

    Julie! hellow!!! So thrilling to have a crime writer here on the blog. Wow!! Oh Please please please dont let the bad guy or victim be an intersex or transperson. There is so much power in the written word… maybe you can be the creator of a hero who is an intersex person. I’d love to see a writer do that! In advance let me wish you the very best for your project. I’ll be cheering for ya!

    Anderson, thank you once more for taking the trouble to write this.

    • J, you always bring such positivity and brightness with your comments. Your comment has also helped me realize that I could have been more gracious to Julie and still made my point. Thank you.

  5. Julie says:

    Anderson and J~

    Thank you so much for your feedback. Anderson, I am not even close to being an expert. I grew up in a very open environment and, as an only child, the information was there for me whenever I was ready, in an honest, open and loving way. The only transgender (called transsexual at that time) I had contact with was very open with me about her transition, and I did not have the impression her decision to make the change had anything to do with an issue physically, so I must admit I’m uninformed in this area.

    Without giving away too much here, my antagonist is a very tortured soul. I would absolutely not handle this in any other way than with the utmost sensitivity, and frankly, I could use your help. I don’t want to get this wrong, and before your feedback I arrogantly believed I could do this on my own. I’d like all the help you’d be willing to give.

    In my first book, Testarossa ( I introduced a transgender character that will be recurring, whom I absolutely love. I hope I did her proud. I believe I did.

    I really cannot talk any more about the sequel openly, much as I’d love to–it’s still in transition. 😉 I have finally found a voice for this antagonist and I’ve found a path, but as you’ve both said, it needs to be handled with great sensitivity. I feel as you do, J, that so much can be done with the written word. It can change lives, or at the very least, inform lives. I’d like to do that here, with your help.


    • Julie —
      Please forgive my poor manners in my previous post. Of course, I hope that your book is successful and I applaud you on wanting to do the right thing and address this situation with sensitivity. Personally, I’m not 100% sure of what ‘the right thing’ would be, but it’s not my book so I am off the hook. 🙂

      May I give you a piece of advice? Although the term ‘transsexual’ can be used as an adjective or a noun, the term ‘transgender’ is only an adjective. So although you knew a transsexual, you did not know a ‘transgender’ — you knew a transgender person. In case you are not familiar with it, here is a link to the GLAAD Media Reference Guide with a transgender glossary of terms:
      And here is the skinny on the use of the word ‘transgender’ from the GLAAD guide:

      PROBLEMATIC: “transgenders,” “a transgender”
      PREFERRED: “transgender people,” “a transgender person”
      Transgender should be used as an adjective, not as a noun. Do not say, “Tony is a transgender,” or “The parade included many transgenders.” Instead say, “Tony is a transgender person,” or “The parade included many transgender people.”

      Also, with regard to this comment:

      “and I did not have the impression her decision to make the change had anything to do with an issue physically,”

      Usually, when a trans person medically transitions, it is because of a physical ‘issue’ in that their body is not congruent with their internal sense of self. In those cases, it’s all about the physical. Gender dysphoria can be painful, sometimes debilitating, and medical transition addresses that.

      I plan to go find a copy of your book so I can check out your writing style and your trans character. There are people in the trans community that keep a running database of books that have content dealing with transgenderism in some way, and sometimes there is commentary along with the book description. I’ll see what, if anything, people in the community have had to say about your book.

      Lastly, you mentioned three times in your comment that you could use some help. I don’t know about J, but I’m intrigued. What does that mean, ‘help’? What would it look like?

      Best regards…

  6. Julie says:

    I was not offended in the least, Anderson. It’s good for me to be reminded that I don’t always know everything. I wrote Testarossa without talking to a single cop because I was a new writer (started late in life:)), and believed their jobs were more important than mine, and I didn’t want to bother anyone. What I found is that all I really need to do is ask, and people are generally more than willing to answer questions, as you were.

    I want my information to be accurate. Having said that, I wrote Testarossa in the first person (man’s voice). John Testarossa is a ex NYPD, now LAPD. He’s tough and not always PC, but he’s got a deep need to connect, and I find him to be more open and willing to understand people more than perhaps we see in most fiction. I have a ‘look inside’ feature on my book on Amazon, and if you search Junie Joo, you’ll find the section that features the transgender character (hopefully). As I said, I hope I did her proud. I love this character.

    Help in the form of what you’ve already done is what I’d appreciate. If you’d be willing to answer questions and advise me on…whatever, I’d be most grateful.

    I understand what you’re saying re: my transgender acquaintance, but what I meant was really ‘physically’, as in… was she AIS. I do not know, but I don’t think so. The mental stuff I get. She explained it all. I was 18 when she did. It was a long time ago. She has since passed away.

    Funny, in all the reviews I’ve received, no one mentions this character. I had one friend, also a writer (of Latino history here in LA), that he liked how I portrayed Latinos in the book–something I never gave a thought to, just wrote what I knew. I was flattered that HE of all people thought I did it right. I’d like to get this right, too.

    The book is very character-driven, the dialogue, to me, very real, and not always politically correct. I wanted to get the ‘cop’ stuff right, because first and foremost it is a crime novel. I’d like to speak to you privately about the direction I see this possible antagonist character going, if that works–and there’s no rush to it. You have a life. 🙂

    Anyway, thanks again for the feedback.


    • Hi Julie,
      Thanks for the links. I had already found most of them but the others were helpful.

      I went to Amazon to see your book. Actually, I had tried to “look inside” before your most recent comment but it kept directing me to the Kindle version so this time I did a less direct search and found the paperback version and was able to get into the book.

      I thought your writing style was engaging — good dialog and interesting main characters, at least in the little bit that I read. I can’t say yet how well I felt about your portrayal of the cop characters because I haven’t read enough of the book to have an opinion, but that’s also something I know a little bit about because there are 4 cops in my family.

      Regarding your request for help, however, I will have to give it some thought. Although I am flattered that you asked and am also a stickler for getting the details correct (and so have an interest in helping with that) I am afraid that I was not enamored with the portrayal of the transgender character in your book. This is not a personal judgment about you, especially after you mentioned that the main character is not PC, and also because there probably are trans women who would match this portrayal, but I found myself thinking when I read the description of the Junie Joo character, “Really? Another transgender woman of color portrayed as a prostitute?” To me, that’s perpetuating the stereotype that trans women are frequently subjected to. I am not a fiction writer and don’t want to presume to tell a writer such as yourself her craft, but I asked myself, couldn’t this character have been just as interesting and flamboyant and on the street at the date and time she was needed in the story without being a hooker? Maybe working with the homeless? Or handing out needles and condoms to fight the spread of HIV? Even an Iraq war vet (as there are quite a few trans women who served in the military before coming out to themselves) suffering from PTSD and living hand-to-mouth on the street, collecting a VA pension. A portrayal like that would have been, for me, more endearing, even valiant, and less stereotypical. Also, I find the term “tranny” offensive, but again, I know that the cop character is not PC and that is likely a term he would use, and also there are trans people who do not have a problem with that term.

      So, you see, it’s a conundrum for me, one that will take some thought on my part in order to decide whether my helping you would be a use of my energy that’s comfortable for me.

      Best regards….

  7. j says:

    Hi Julie!
    Sorry I replied a little late. I’m in a different time zone. Thank you for your biography. It was very inspiring to read how you had the courage to make a career change. And how you’ve balanced career and family.

    Julie, I share your sentiments over steroid use. The pressure on athletes is crushing. Since your boys have your support, I know they will remain anti-steroid.

    Well, all the very best with your book. It’s been a pleasure and delight getting to know you!!!! I wish you every success!!!

  8. Julie says:

    Thank you, J. That was very sweet of you.

    And Anderson, no problem. Whatever you’re comfortable with. I appreciate all you’ve done.


    • Thank you Julie. As always, J has captured the human element better than I and brings great balance to this blog. I echo her sentimments and will contact you directly through email with my decision. Best wishes…

  9. Julie says:

    Anderson, that’s OK. If this causes you even two seconds of hesitation, lets move on. You’ve answered my questions and I appreciate it. This is simple stuff, just two people conversing. What you’ve given me is enough and I thank you.

    Take care.


    • Thanks Juilie. I guess I am uncomfortable with both the trans and the intersex characters. All the intersex people I know (some of whom are in my family) are not violent or ‘tortured souls.’ They’re just regular people like everyone else. Probably best to move on, as you say.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s