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Understanding the Genetic Mutations and Interactions that Cause Cleft Lip with or without Cleft Palate



What is IRF6 and why was it important for you to look into this gene’s activity?

The IRF6 gene is arguably one of the most significant contributors to the incidence of, and susceptibility to, cleft lip / palate. It encodes a protein, called a transcription factor, that functions in the nucleus of cells to turn on other genes. It primarily functions in epithelia, particularly in the developing embryo. It is a member of a small family of proteins, called interferon regulatory factors, that also have a role in immunity.

What was the underlying theory of your research and how did you go about studying it?

We really wanted to understand what controls IRF6 under the premise that we would not only better understand its role in the embryonic facial epithelia but also identify other factors that may contribute to the incidence of CLP. We went about this using what is known as a bait’n’prey system in which we use one protein (in this case IRF6) as a bait to try and capture and identify other proteins within the cell that bind strongly to it – since all proteins carry out their functions by interacting with other proteins.

What are the findings of your research?

So we ended up finding a number of interacting proteins. Some of these, as we expected, represent proteins that also bind DNA and similarly act as transcription factors. However, two related interacting proteins that were found were proteins that had been shown previously to function near the cell membrane to control the dynamics of how epithelial cells adhere to each other. This drew our particular attention for a number of reasons: 1) cell adhesion is known to be important for the development of the lip and implicated in the pathogenesis of cleft lip/palate, and 2) it was known that IRF6 is mostly found outside the nucleus of the cell and its import into the nucleus is tightly controlled. So we wondered whether these new interacting proteins and IRF6 were somehow forming a novel complex inside the cell to regulate each others function. And indeed we showed that this is the case. Further, we tested whether this new protein complex had an essential role in formation of the lip by analyzing these two new genes in patients with cleft lip/palate. We found two unrelated patients who carried mutations in the new genes and we showed that these mutations disrupted the ability of these respective proteins to interact and regulate IRF6.

How are these findings translated into clinical practice and can they be used in either the genetic correction or management of this facial anomaly?

Our studies have provided new insight into how one of the most important cleft lip/palate genes is controlled and showed that IRF6 has a more direct role in the regulation of how epithelial cells in the embryo adhere than it was previously thought. So what implications does this have for clinical practice? Well, first these data have allowed us to focus our efforts on a particular cellular process. Our earlier work on IRF6 in mice showed that loss of this gene not only could result in cleft lip/palate but also an array of dental anomalies (including hypodontia, agenesis, supernumerary teeth, taurodontism, and mild enamel hypoplasia) as well as altered salivary gland development and function. These additional oral/dental defects were shown to be primary abnormalities. Ultimately we showed that, as a consequence, these individuals showed a significantly increased susceptibility to caries, periodontitis and alveolar bone loss. Our recent work to identify how IRF6 is controlled and what cellular processes it participates in now gives us the opportunity to examine whether we can mitigate the impact of the genetic defect. Knowing the additional genetic factors involved may also help to identify those patients who are most at risk of longer-term dental problems, especially later in life long after the oral cleft has been repaired. In the absence of a current means to correct the genetic defect, it does highlight that patients with cleft lip/palate should be monitored more closely and regularly, and appreciate that dental issues they experience as a teen or adult may well be related to the genetic basis of the oral cleft at birth.

Are there limitations to your research? How far is genetic research from preventing such anomalies from happening?

Yes. There is much to do. Our ongoing research, which hopefully will be published shortly, has led to the discovery of a host of new cleft lip/palate genes. The exciting part of this, other than the prospects for more accurate counseling of patients, is that we are further narrowing down on the molecular and cellular mechanisms causing cleft lip/palate and we are finding other major cleft genes also play an important role in tooth and salivary gland development. So we wish to determine whether the massively heightened caries and periodontitis susceptibility is a feature shared by all genetic causes of cleft lip/palate or whether there are subtypes that are more at risk. I believe this will have an enormous impact on treatment of the prominent patient group as well as potentially their family members who may also carry the genetic susceptibility but not present with an oral cleft. Furthermore, the additional information we are gathering from our ongoing research is highlighting a molecular pathway that is known to be sensitive to various external factors including specific dietary components. So we are pursuing this avenue as it may offer a simple preventative measure for some of the severity of the condition.

Full Interview (14.12″)


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