Autosomal Recessive Disorders

by Georgina Cornwall, PhD

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    00:01 So, I saved the best for last as far as chromosomal disorders are concerned. In this lecture, we’re going to explore disorders of the sex chromosomes, both full polyploidies, aneuploidies as well as structural disorders of the chromosomes. Sex chromosomes kind of work in a slightly different way. So, it seems fitting to put them altogether. The first question we have to consider is how do sex chromosomes actually determine the sex of an individual.

    00:33 It turns out it’s not quite as simple as having an X and a Y. We can have XY individuals that do not appear as a male at all. In fact, somebody has said that, one author has said that there are up to seven different sexes when you consider all the steps along the way at which sex can be determined. There are four discreet steps in the determination of the final sex of an individual. First of all, there’s the chromosomal sex determination, whether you have an X and an X, or an X and a Y. Then we have to consider gonadal sex determination, what sort of gonads is one going to have. Are they going to have ovaries or a testis or ovotestis or one of each? All of those are possibilities. Then we have the differentiation of the external genitalia. Once the gonads have developed, what then happens in order to have the genitalia, internal and external genitalia become either male or female or a mixture of both? Finally, are the development of secondary sex characteristics. Along the way, lots of different mistakes can happen.

    01:51 In fact, if we were to talk about brain chemistry, we could discuss the exposure to different environmental stimuli that actually impact some of the brain developments associated with these disorders also. But we’re not going to go into that much detail.

    02:10 But that is a fascinating field to me. The first chromosome I’ll introduce you to is the Y chromosome. You’re probably pretty familiar with it as being a male chromosome.

    02:23 The Y chromosome, even though X and Y are non-homologous chromosomes, they are still a pair of chromosomes. It turns out that they actually do have pairing and crossing over in the pseudoautosomal region. Pseudoautosomal because it’s not an autosome, it’s a sex chromosome. In the Y chromosome, that’s located up at the very, very tip.

    02:50 It’s the blue region at the very tip of this chromosome in which the Y could cross with the X.

    02:57 On occasion, it does. Then on occasion, things get a little bit screwed up and they cross somewhere in the non-pseudoautosomal region. That’s when we’ll see movement of male determining genes and such. We’ll be exploring that stuff shortly.

    03:16 The key piece of the male chromosome and some might argue it’s the only really important piece on there is the SRY gene, SRY meaning sex determining region of the Y chromosome.

    03:30 The SRY gene produces a product that is called testis determining factor. It’s very nice that we’re keeping the names pretty simple for these disorders. Testis determining factor is the product that’s produced by SRY gene that may eventually end up causing the development of testis and perhaps all the other downstream things from there. But of course, because we are talking about medical genetics, we are going to look at some disorders associated with the sex chromosomes. There are multiple regions that you can see outlined on the sex chromosome that are associated with DSD's which is disorders of sexual development.

    04:20 DSD's, disorders of sexual development, we will be exploring a number of different ones.

    04:27 But first of all, let’s look at how Y functions in sex determination. To start with, I’ll let you know that the default sex is female. If nothing happens, this ambiguous gonad or primordial gonad is ambipotent, and if nothing happens, it will develop into an ovary. All the respective downstream things will happen after the ovary secretes estrogen and so on and so forth. We’ll look at that.

    05:00 But this primordial gonad has a paramesonephric duct and a mesonephric duct. The older names are Mullerian and Wolffian ducts based on the people who first described them. These two ducts, the mesonephric duct will be maintained if one of the keys is there or the paramesonephric duct.

    05:29 So, one of them will be reduced. We’ll look at both examples here shortly. Here we are at six weeks in utero where all of the sex determination stuff starts. Before a whole lot of other things have happened, we’ll see that there’s migration of cells and production of this ambipotent primordial gonad. Now, if there’s a Y chromosome present and that Y chromosome has an SRY gene that is functioning, then we may get testis determining factor from that. That may end up giving us testis or giving the individual testis, which will secrete testosterone perhaps.

    06:24 There will also be anti Mullerian hormone created that will cause recession of the Mullerian ducts and growth or support of the Wolffian ducts. Eventually, we may get male genitalia.

    06:43 Hopefully, if nothing else, this whole scheme tells you all the different steps along the way at which something could go wrong which is why I say might. Sometimes when I think of this, I honestly question, how do we ever actually get a male to come about because there are so many steps along the way and the female step is so simple. If none of this happens, then we end up with female.

    07:10 In the case that there is no Y chromosome, or there is no SRY, or testis determining factor doesn’t happen, or anti Mullerian hormone doesn’t happen, then by the time we get to eight weeks, ovaries develop, estrogen is secreted, and the mesonephric ducts are supported because we don’t have the anti-mesonephric or Mullerian hormone. We have female genitalia. There we go, female development from the ovary through external genitalia, fairly easy; development of Y, fairly complex. You’ve probably all heard this in several different courses because it’s definitely a component of anatomy and physiology. But here, we’re looking at where things could get upset with genetics because guess what? All of these things including the estrogen are coded for by genes that produce proteins that either make them or are them, so testis determining factor and whether the SRY gene is in place or not. So, that’s one of the critical components.

    About the Lecture

    The lecture Autosomal Recessive Disorders by Georgina Cornwall, PhD is from the course Chromosomal Disorders.

    Included Quiz Questions

    1. Maternal age at conception
    2. Chromosomes
    3. Gonads
    4. Genital differentiation
    5. Development of secondary sex characteristics
    1. At the pseudoautosomal region on short arm p
    2. At the nonhomologous region on long arm q
    3. At the pseudoautosomal region on long arm q
    4. At the nonhomologous region on short arm p
    5. At the heterochromatic region on the long arm q
    1. Week 6
    2. Week 4
    3. Week 12
    4. Week 1
    5. Week 9
    1. Phenotypic female with female genitalia
    2. Phenotypic male with female genitalia
    3. Phenotypic female with male genitalia
    4. Phenotypic male with male genitalia
    5. Phenotypically female with both male and female genitalia
    1. Mesonephric ducts differentiate in response to testes determining factor.
    2. Paramesonephric ducts develop in response to testes determining factor.
    3. Mesonephric ducts reduce in response to testes determining factor.
    4. Paramesonephric ducts develop in response to antimullerian hormone.
    5. Paramesonephric ducts develop in response to antiwolffian hormone.

    Author of lecture Autosomal Recessive Disorders

     Georgina Cornwall, PhD

    Georgina Cornwall, PhD

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