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Cleft Lip and Palate: Van der Woude Syndrome

Media: The Inside Scoop


October 2002

After a nearly 20-year search, a team of scientists report in the October 2002 issue of Nature Genetics that it has discovered a gene involved in causing Van der Woude Syndrome, the most common form of syndromic cleft lip and palate. The Inside Scoop recently spoke with two authors on the paper: NIDCR grantees Jeff Murray, M.D., and Brian Schutte, Ph.D., both of whom are scientists in the Department of Pediatrics at the University of Iowa. They shared their thoughts on the difficulty in identifying the Van der Woude Syndrome gene, the possible scientific benefits of studying twins, and the implications of this gene discovery on the more common non syndromic cleft lip and palate.


When did the search for the Van der Woude Syndrome gene begin?

Murray: The search began around 1985, at least for our group. At that time, the tools had improved to search for genes involved in "single gene" disorders, that is, where a change in a single gene causes an inherited condition. Van der Woude Syndrome is the best example of a single-gene disorder that causes cleft lip and palate that looks like the "non-syndromic" form, one of the most common birth defects in the world.

In 1990, your group narrowed the search to a specific segment of chromosome 1. Over the next several years, you searched this region and excluded a number of candidate genes as the cause of Van der Woude Syndrome. One of these genes was IRF6, the subject of this month's paper. What lead you to reject it originally in the mid-to-late 1990s?

Schutte: Indeed, IRF6 was one of the first genes that we found while sequencing this region. By coincidence, scientists in Toronto contacted us about this time to say they had identified the mouse version of IRF6 and also had a partial copy of the human gene transcript for IRF6. This gave us the needed research tools to search for possible mutations in this gene, and we began searching almost immediately with a technique that is not absolutely sensitive to changes in the DNA sequence, but which had been successfully for many other gene discovery projects. We tested DNA samples from a subset of people with the syndrome, and we found nothing to indicate that it was the VWS gene.

About this time, the full-sequence map of the region became publically available through our collaboration with the Sanger Centre in England, one of the sequencing centers for the Human Genome Project. It allowed us to see for the first time where all of the genes within the region were located. We suddenly had a long list of other genes to evaluate and had to move on from IRF6. Part of our reasoning was IRF6 belongs to a family of genes called "interferon regulatory factors. We assumed this gene, like the other members of the IRF family, was involved in regulating interferon, a signaling molecule of the immune system, and had nothing to do with cleft lip and palate. In this case, the name turned out to be a misnomer.

Murray: Another point. At the time, we understood that we were excluding candidate genes that could still potentially be the disease gene. But you always have to choose the best place to focus your efforts, and our data at the time indicated that it was better to move on to other candidate genes.

Is this a case of too much information? That is, you had too many candidate genes to sort through at one time?

Schutte: In this case, the large volume of information turned out to be a mixed blessing. The full DNA sequence was a tremendous help in accelerating our search for the gene. It was absolutely invaluable in letting us know what was and wasn't there. But, as this scenario indicates, labs can never be exactly sure of what they're excluding.

The turning point in the gene search was clearly the twins. How did you find them?

Murray: I have a collaboration with researchers in Brazil. One of their graduate students worked in my lab for a year doing a research project, and she knew that we were very interested in VWS. One day, she was talking on the telephone to one of her clinical colleagues in Brazil. Her colleague happened to mention that he had just seen a pair of so-called "monozygotic" twins, in which one had Van der Woude Syndrome and the other didn't. She told us about it, and we got quite excited.

Why did you get excited? Was the idea, because they were identical twins, all you had to do was find the one mutation in the affected twin?

Murray: Right. I certainly knew it was possible in theory. But, if I knew as much then about twins as I do now, I would have been a lot less excited. The reality is we still could have missed the mutation even with the twins. For the theory to pan out, it required that the mutation occur very early after the twins divided into two separate embryos. If the mutation had occurred a little bit later, that is, after the stem cells had differentiated into distinct cell lineages, we might have missed it. The mutation would have been present in some, but not, all of the cells in the body. So, there certainly was a little bit of luck involved.

For the scientific community, I think the twins are the most important point of this paper. Monozygotic twins are actually quite common in other complex conditions, such as diabetes and heart disease. I think our work offers proof of principle that monozygotic twins are a powerful model to search for genes involved in complex conditions, one that might have been overlooked in the past.

How many genes already have been identified that are involved in cleft lip and palate?

Murray: For the syndromic forms, there's been somewhere in the neighborhood of 15 to 20 genes that have been identified. All of these genes, when inherited in altered forms, can cause a cleft and other physical abnormalities. For the more common non-syndromic forms, there have been some strong genetic hints provided for three or four genes. But there is really only one for which anyone could make a strong case that a family that looks like it has non-syndromic clefting has a mutation in that gene. That was a study that was done in Holland about two years ago for a gene called MSX1.

How does IRF6 fit into the big picture of understanding cleft lip and palate?

Schutte: Van der Woude Syndrome is the most common of the syndromic forms, accounting for about 2 percent of all cases. It also is the syndromic form that is most similar to the non syndromic. For this reason, it has always stood out as a key piece to the puzzle of cleft lip and palate.

What do we know about IRF6?

Schutte: Almost nothing is known about IRF6, other than it has the structure of an interferon regulatory factor gene, or IRF. The good news is scientists have been characterizing IRFs since the early 1990s, and that is why we can pretty much guess what it does. We know that IRF6 is a transcription factor, meaning it binds to certain genes and allows their information to be copied, the first step in producing a protein. We can now ask which genes it activates and when? All of these genes might be involved in causing cleft lip and palate. Or, they could contribute to other birth defects. The point is we stand to learn a great deal from this gene discovery.

What might the gene tell us about the non-syndromic form of cleft lip and palate?

Murray: This particular gene provides us with what we call a candidate to look at non-syndromic forms of clefting. It also allows us to study at a genetic level whether IRF6 could be involved directly in non-syndromic clefts, or whether it could work as a modifier, that is a gene that by itself doesn't cause the cleft, but which might affect the severity of the cleft. Since there is so much clinical overlap between the two, we expect similar genes and maybe even the same genes will be involved in the non-syndromic form. Finding one gene is important because that single gene clearly plays a role. But the gene is probably even more important in the long run because it now suggests that other members of that family or of that pathway may also be involved in the non syndromic form.

I think it was mentioned that the gene might also suggest a viral link in the cause of cleft lip and palate?

Murray: Right, it's purely speculative at this point. Because this gene belongs to a family of genes that are generally involved in the immune response to viral infections, I'm interested in whether viral infections early during pregnancy may play some role in causing cleft lip and palate. Although there is no strong evidence to support the idea at this time, there is a little bit of evidence that suggests it might be the case. This would be a wonderful outcome of this paper because, in 2002 at least, attacking viruses is much easier than manipulating genes.

So much of the focus is on finding genes and mutations, but you couldn't have found anything without the families. Correct?

Murray: Exactly. We've just had extraordinary cooperation from families and clinicians. The clinicians, for instance, typically get no personal benefit for referring patients to a research study. In fact, it usually involves extra time, for which they are not reimbursed. The same is true with the families. Family members donate their time to give samples, which some people don't always like to do. I would add, the reason that we could move so quickly from finding the gene to very overwhelmingly proving its role in the syndrome is we have a bank of DNA samples from over a hundred families. We would have never been able to move that quickly otherwise.

Clearly, you made the families a priority--

Murray: Yes, I think right from the start we realized how valuable the families are. They are valuable not only as the source of the research, but also in how much of a commitment that you have to them. Some of these families are desperate to help an affected child. For me, the hard part as a scientist is you know that the research time frame is a long one. Even when you make an exciting discovery like this one--and we think it is exciting--it doesn't mean that prevention strategies or better treatments are going to happen next week. It may still be years and years and years before it is converted into a new treatment. You feel so connected to the families. You feel so motivated to continue the work because you hope that, for the children of the children, there will be something better for them one day.

And you know that you are headed down the right road and in the right direction.

Murray: Absolutely. I very much believe that.

October 2002

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This page last updated: February 26, 2014