University of Manchester researchers have uncovered the causes behind two genetic conditions that lead to facial anomalies including clefts, where the lip and often the roof of the mouth, or palate, fail to form properly.
Working with colleagues at the University of Iowa, Manchester husband and wife team Mike and Jill Dixon together with researcher Rebecca Richardson, have identified the role of a gene called IRF6.
"We had previously shown that a mutation in the IRF6 gene causes Van der Woude syndrome – a rare inherited form of cleft lip and palate," said Professor Mike Dixon, a dentist based in the Faculty of Life Sciences.
"It has also been found that defects in this gene are responsible for a significant number of other cleft lip and palate disorders that are not related to any particular syndrome."
The team established that mice missing the gene developed abnormal skin as well as cleft palate. Further analysis revealed that IRF6 controls the development of keratinocytes – the main type of cells in the outer layers of the skin, known as the epidermis.
"Put simply, mutations of IRF6 in Van de Woude syndrome make the skin cells too sticky, so they stick to each other and other types of cell much sooner than they should resulting in these facial anomalies," said Professor Dixon.
The findings – published in the journal Nature Genetics this week – surprised the researchers, as all other genes in the IRF family have completely different roles, primarily in the body's immune response.
"This unexpected role for IRF6 in skin development may mean it is involved in other medically important areas of biology such as cancer and wound healing.
"In any event, this research has the potential to lead to new ways of treating cleft lip and palate caused by this genetic mutation, as targeting the defective gene during pregnancy could help the skin cells develop normally."
Further research by the Manchester team, this time with scientists at the Stowers Institute for Medical Research in Kansas, has uncovered the cellular processes involved in another genetic disorder that results in cleft palate.
Treacher Collins syndrome is characterised by underdeveloped jaw and cheek bones and ear anomalies, as well as cleft palate.
Whereas cleft lip and palate remains the most common form of congenital abnormality, affecting one in 1,000 babies in the UK, Treacher Collins syndrome is a relatively rare genetic disorder affecting one in 50,000 individuals.
"We identified the gene associated with this disorder some time ago but we have now established the reason for the anomalies," said Dr Jill Dixon.
"Working with a mouse model, we found that the craniofacial disorders are caused by the high number of cells, known as neural crest cells, that die before they have migrated to form the bone, cartilage and connective tissue in the face and head of the unborn animal.
"When translated to human development, this failure to produce enough neural crest cells in the first three to eight weeks of pregnancy results in the craniofacial anomalies observed in Treacher Collins syndrome."
Dr Paul Trainor, who headed the Kansas team, said the findings – published in the Proceedings of the National Academy of Sciences (PNAS) – were an exciting step in their investigations of genetic birth defects.
"In ongoing studies in the lab, we are testing a number of methods for chemically and genetically inhibiting the early period of cell death in an effort to stimulate the production of neural crest cells which could help to prevent the development of craniofacial anomalies."
Dr Robb Krumlauff, Scientific Director at the Stowers Institute, added: The results represent a major breakthrough in our understanding of Treacher Collins syndrome. But the door that these findings open – to the possibility of intervening in utero to prevent the disease – is truly groundbreaking."
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