Clue to Genetic Cause of Fatal Birth Defect

UIC Podcast
UIC Podcast
Clue to Genetic Cause of Fatal Birth Defect

News Release


[Writer] This is research news from U-I-C – the University of Illinois at Chicago.

Today, Geula Gibori, distinguished university professor in physiology and biophysics talks about her discovery of a novel enzyme and the surprising role it seems to play in anencephaly.  This may offer hope for a future genetic test and possibly therapy for the rare fatal birth defect in which the brain fails to develop.

Here’s Professor Gibori:

[Gibori] My interests are about genes and their regulation involved in pregnancy.  Some years ago, we discovered a protein, highly expressed in ovaries, which wasn’t known before.  We cloned it, we sequenced it and found out that it’s a novel protein.  However, we found a signature in this protein which may indicate that it is an enzyme.  So we checked whether it was an enzyme and found that it belonged to a family of enzymes.  Our lab and the Vihko lab in Finland found that it is an enzyme that converts weak estrone, which is an estrogen, to the very potent estrogen known as estradiol.  So we were very excited because in the ovaries, estradiol plays a key role and is important for the maintenance of pregnancy.

At this time, we also found that this enzyme, which is highly specific to the ovaries, is also expressed in breast cancer.  Very little – almost none in a normal breast – is highly expressed in breast cancer cells.  Since it makes estradiols and estradiol causes breast cancer in a large majority of cases, that’s become of interest to us.

At the same time, another group in Germany discovered that this enzyme doesn’t only convert the weak estrogen to the very potent estrogen, but also is the enzyme in the synthetic pathways – that means in the synthesis of estradiol.  The synthesis of estradiol involves several enzymes – one of them was not known until they established that this is the enzyme which involves cholesterol.

At this stage we poo-pooed the cholesterol effect of our enzyme because the ovary has plenty of cholesterol from the maternal circulation and doesn’t need to synthesize cholesterol to function.  But we decided because this enzyme became of interest to delete it, remove the gene from mice, and see what happens.  What we expected was to see the mice born normally, and to be infertile.  We also wanted to see if cancer was difficult to induce in those mice because of the lack of this enzyme.

However, what happened is we found out that the fetus was dying in utero – they died before they were born.  It was really strange to us.  They were dying at the age of 10 days.  Now what normally happens at the age of 10 days is, normally the baby receives cholesterol from the mother, and doesn’t need to synthesize it to grow and develop.  The only tissue that depends on the synthesis of cholesterol is the brain.

What happens on day 10 is the brain develops a barrier that prevents to cholesterol from the mother to reach its cell.  So now the brain needs to synthesize cholesterol.  And if it does not synthesize cholesterol, it looks like it doesn’t form.  The only thing that was known was that you needed to synthesize cholesterol, and what we’ve found is that this enzyme that we totally accidentally discovered in the ovaries plays a key role in the formation of the brain.  Once you remove it, you have no brain which forms.

What’s interesting to us is anencephaly, or lack of brain, has been known in humans for years.  The percentage of babies born without brains are rather significant and, obviously, no solution is known to date because nobody knows what are the real causes of anencephaly – what is the gene involved in anencephaly?

Our discovery that the removal of this gene in mice causes the brain not to develop at all at the time when the brain depends on cholesterol biosynthesis, led us to think that we may have discovered at least one of the reasons for anencephaly in humans.  What we want to know now, and we’ve made connections with many centers – and Isabelle Wilkins here at the University of Illinois will provide us with tissue from an anencephalic baby – because in anencephaly in humans, the baby either dies in utero, or can be born and then die up to several weeks after they are born.

Naturally with the permission of the parent, we (request) whatever tissue from the baby – even hair – and we want to determine whether the baby was born without a brain (and) lacks this enzyme we discovered, or the enzyme can be mutated and therefore cannot produce the protein necessary to form the enzyme.  And we hope with all our heart that we have discovered this gene, because once you know the reason, in the future you may find a solution to the problem.

[Writer] Geula Gibori is a distinguished university professor in physiology and biophysics in the UIC College of Medicine.

For more information about this research, go to … click on “news releases.” … and look for the release dated Oct. 9, 2008.

This has been research news from U-I-C – the University of Illinois at Chicago.

Print Friendly, PDF & Email