The face predicts the brain

Craniofacial anomalies or malformations of the face and skull account for approximately one third of all birth defects. The most common among them is the failure of the forebrain to complete the division into the double lobes of the brain’s left and right hemispheres, a condition known as holoprosencephaly (HPE). Not all individuals with HPE are affected to the same degree, but in many patients it is closely associated with facial malformations, such as a flattened midface, closely set eyes, as well as clefts of the lip and roof of the mouth. Currently, it is not known whether these defects share a common origin, since only about 20 percent of HPE cases can be attributed to a specific genetic mutation. For all others, the cause remains unknown.

Serendipity led Jennifer Dennis, PhD, a former graduate student in Investigator Paul Trainor’s lab and now an assistant professor at the University of Kansas Medical Center, to the discovery that hedgehog acyltransferase (Hhat) plays an important role in craniofacial development. Dennis found that a mouse line already being used in the laboratory unexpectedly carried mutations in Hhat, and that embryos derived from these animals suffered from holoprosencephaly together with a partial absence of skull bones and an underdeveloped or completely absent lower jaw mimicking the severe human condition.

Hhat helps with the processing of Sonic hedgehog (SHH), a protein that is required for the proper migration and survival of neural crest cells. These cells generate most of the cartilage, bone, and connective tissue in the head and face, explaining the link between cranial and facial malformations. “Our work provides new insight into how the most severe craniofacial birth defects may arise and identifies a new gene to screen in humans born with this condition,” says Dennis.

The study was published in the October 4, 2012, issue of PLoS Genetics.