Autosomal Disorders and Genomic Imprinting

00:01 I promised this in an earlier lecture. We’re going to now revisit genomic imprinting. Genomic imprinting can be fairly tough to understand.

00:10 And these are two conditions that we are certainly going to need to know about for the USMLE exams, Prader-Willi syndrome and Angelman's syndrome.

00:21 Again, genomic imprinting occurs when the expression of a deletion is different depending on the parent of origin. So both these syndromes result from a microdeletion on chromosome 15. However, the expression is completely different dependent on which parent that chromosome was inherited from.

00:48 So before we dive all the way into it, I wanted to take a quick review of the genomic imprinting scenario. So we’ll review this.

00:58 This figure should look pretty familiar. The parent of origin is the thing that we need to consider here. So we’ll again start with the top of the figure.

01:09 We’re showing an oocyte, sort of on the central right hand side that has a pink chromosome in it.

01:17 That chromosome is marked as being from the mother and has certain region on it that is imprinted, epigenetically modified so that certain region of that chromosome is not expressed.

01:31 And when that ovum is fertilized by a sperm, it is going to be fertilized by a sperm who also has a chromosome that has been marked as from the father, so from the sperm.

01:48 And it has a region that has also been epigenetically modified to mark it as non-expressed region of that chromosome.

02:00 Both of these chromosomes will end up in the embryo. And they are marked as paternally inherited or maternally inherited.

02:10 And then those cells will continue to divide and an adult carries the same marked chromosomes.

02:20 So, is that clear? With those same marked chromosomes then, the adult will have germline cells.

02:29 Which we see here at the side closest to me.

02:33 And those marked chromosomes become unmarked.

02:39 So the epigenetic markers, the hypermethylation of those specific regions is removed.

02:46 And then as the gametes form, they become re-marked as that parent of origin as you see here illustrated by the two chromosomes becoming pink, having the maternally unexpressed region imprinted or hypermethylated, or having the paternally unexpressed region hypermethylated.

03:13 So now, they are specifically marked in a different region by hypermethylation for non-expression of that region.

03:26 So are you with me on that because we’re going to get a little bit more complicated.

03:32 Let’s look at this in a little bit more detail. Here at the top, we have chromosome number 15.

03:39 The region in blue is marked as the region that is expressed on the paternal chromosome, not the region that’s hypermethylated.

03:50 The Prader-Willi syndrome region is named for the syndrome because it was discovered for the syndrome.

03:59 So it’s a little bit backwards. You’ll see. The Prader-Willi region is expressed on the paternal chromosome. And that’s why we have it pictured in blue.

04:07 And then the Angelman's syndrome region is only expressed in the maternal parent. The congruent regions on the other chromosome are going to be hypermethylated. So, we have the expressed region on the paternal chromosome is hypermethylated on the maternal chromosome.

04:37 And that hypermethylation is what imprinting is. So to me, this has always been kind of opposite.

04:44 You would think it was imprinted to express like when we think of printing, it’s writing, it’s expressed.

04:49 But it’s the opposite of that.

04:52 So, if you can keep in mind that the Prader-Willi region is actually expressed only by the paternal chromosome and deletion of that region on the paternal chromosome is going to result in non-expression of that region. So, I’ve made a summary slide here to put it all together because I promised you.

05:19 As you go through Angelman's and Prader-Willi and try to sort them out, you’re probably going to get yourself confused. At least, I do, fairly often when I go to lecture on this topic.

05:32 So the first point is that genes expressed are only on the paternal chromosome and maternal chromosome.

05:40 Those are the areas marked in pink and blue.

05:42 The second piece of this is that each region that is hypermethylated, this is the imprinting piece or the turned-off piece.

05:51 So, hypermethylation, imprinting, turned-off, all the same word on the opposing chromosome.

06:00 So thus when we have a deletion on the region that is expressed on either the paternal or maternal chromosome, there are going to be none of those genes expressed.

06:13 And thus will have either Angelman's or Prader-Willi depending on which chromosome has the deletion.

06:20 You got me? Because I swear, I have to wrap my head around this over and over.