New explanation for the genetic mechanism that triggers cleft lip and palate
BONN, Germany/PHILADELPHIA, US: Though it was known for long that the TP63 gene can contribute to the development of cleft lip and palate, the exact process was unclear. A recent joint study by the universities of Bonn and Pennsylvania has clarified this mechanism of action.
About one in 500 births in Europe and one is 700 births worldwide are known to be affected by cleft lip and palate. They occur due to a developmental anomaly that appears in the early weeks of embryonic development, which causes parts of the face or palate remain unfused.
For quite some time, it has been known that mutations of TP63 gene can trigger the severe forms of cleft lip and palate. Clinically, the features are not only limited to the formation of gaps in the facial area, but also involve the malformations of the extremities and diseases in the skin, hair and tooth area. Generally whenever such features are combined together, a term known as ‘syndrome’ is assigned to the overall condition.
Originally TP63 was thought to be playing a role only in the development of this "syndromal" form of the cleft lip and palate. However, in the last two years, there are increasing indications to suggest that this is not true. Dr. Kerstin Ludwig from the Institute of Human Genetics of the University Hospital Bonn says "In our work, we were able to show for the first time that TP63 is indeed a link between the syndromal and the isolated form, and how it intervenes in facial development."
This international collaborative study involved researchers from the University of Pennsylvania, who were able to "program" human cells in culture into facial cells. This facilitated the evaluation of the effect of TP63 gene on this particular cell type. This data was then blended with genetic data of large patient cohorts by the Bonn researchers. "We were able to show that TP63 increases the activity of a whole series of genes that play a role in the development of isolated forms of cleft lip and palate," says Ludwig.
Chromatin is a complex of DNA and various proteins present inside the cell nucleus. It is a long thread bundled into a compact ball. TP63 attaches to this chromatin thread and loosens the compact ball, which along with other modifications, causes a particular gene in this region to be read more frequently.
“According to current knowledge, TP63 regulates several thousand locations in our genome in this way,” said co-author Dr Julia Welzenbach from the University of Bonn. “Among them are 17 which, as we already know from large genetic studies, are involved in the formation of scissures and a large number of other regions whose involvement was previously unknown.”
The observation that TP63 activates a large number of regions shows the importance of this gene in humans. A mutation that affects its function severely, would automatically affect a large number of organs as well. This was the reason why TP63 was originally associated with only the syndromic form of cleft lip and palate. “In the case of the non-syndromic form, however, its disturbing activity is limited to developing facial cells,” said Ludwig.
The newly established cell system provides a tool that enables the researchers to investigate this disorder in greater detail and identify its biological causes. “For example, we could test the effect of different environmental factors on TP63 activity in facial cells,” stated Ludwig.
Environmental influences are known to increase the risk of facial malformation. Scientists can apply such tests to families that are known to have a genetic predisposition and provide them with recommendations for better individual prophylaxis.
The study, titled “p63 establishes epithelial enhancers at critical craniofacial development genes”, was published in the May 2019 issue of Science Advances.