Credit: Brandon Laufenberg

Treacher Collins syndrome (TCS) is a craniofacial development disorder that affects roughly 1 in 50,000 people. It is characterized by underdeveloped facial bones, which frequently results in a sunken appearance in the middle of the face, a prominent nose, a very small jaw and chin and downward-slanting eyes; some affected individuals also have cleft palate and malformed or absent ears. Now, researchers have found a way to prevent development of the disorder in a mouse model by inhibiting the function of p53, a tumor suppressor protein.

TCS is caused by a mutation in the gene TCOF1 that causes death in neural crest cells early in embryogenesis. In normal development, these cells would form the bone, cartilage and connective tissue of the face. The new research, led by Paul A. Trainor (Stowers Institute for Medical Research, Kansas City, MO), used mice genetically modified to model TCS. Trainor's group showed that inhibition of p53 prevented the death of neural crest cells and the resulting craniofacial anomalies in these mice (Nat. Med. published online 03 February 2008; doi:10.1038/nm1725).

Trainor and his colleagues did a series of experiments to map the connection between p53 and TCOF1. They tested two ways of inhibiting p53: a chemical inhibitor called pifithrin-α, and genetic inactivation of one of both copies of the gene encoding p53. Both methods successfully stopped the death of neural crest cells and prevented craniofacial malformation and neonatal mortality.

Trainor's work suggests that inhibition of p53 function might be able to prevent TCS in humans, as well as offer therapeutic potential for other types of congenital craniofacial anomalies. Natalie C. Jones, first author of the report, stated, “The successful rescue of neural crest cell development in a congenital craniofacial anomaly such as TCS is exciting because it provides an attractive model for the prevention of other craniofacial birth defects of similar origins.”

The treatment did have at least one drawback: loss of p53 function was associated with the development of spontaneous tumors in mice. The authors have not identified any humans with TCF who also have tumors. Future research in this area might include identifying therapeutic targets that do not carry a risk of tumorigenesis, such as proteins that work with p53.