Whitehead Institute scientists have identified a genetic cause of a facial disorder known as hemifacial microsomia (HFM). The researchers find that duplication of the geneOTX2 induces HFM, the second-most common facial anomaly after cleft lip and palate. HFM affects approximately one in 3,500 births. While some cases appear to run in families, no gene had been found to be causative. That is until Whitehead Fellow Yaniv Erlich and his lab set out to do just that. Their work is described in this week’s issue of the journal PLOS ONE.
Patients with HFM tend to have asymmetrical faces—typically with one side of the upper and lower jaws smaller than the opposite side—a smaller or malformed ear on the affected side, and, in some cases, neurological or developmental abnormalities. Thought to be brought on by circulation difficulties during embryonic development, HFM is also thought to be sporadic—meaning that it occurs spontaneously rather than through inheritance. However, one family in northern Israel has more than its share of the anomaly.
To identify the origin of this family’s disorder, Erlich and lab technician Dina Zielinski began studying the genomes of a five-year-old female member of the family, along with those of her mother, grandmother, and male cousin, who all exhibited traits of HFM. Later, the genetic information from the grandmother’s Russian cousin, who resides in the Philadelphia area, was recruited to the study.
“What’s unique here is that this is the largest family with this disorder described in the literature,” says Erlich. “Most of the time, you see one person affected, or perhaps two people—a parent and a child. Such a large family increases the power of the genetic study and clearly signals that there is a genetic component to a disease.”
Within this large piece of DNA, Zielinski identified eight candidate genes that could cause the type of HFM running in this family. She then used two algorithms to compare the molecular signatures of these eight genes to other genes known to be responsible for various facial malformations with features similar to HFM. After this analysis, the gene OTX2 that codes for a transcription factor rose above the seven other candidates.
These results are supported by what is known of OTX2’s function. Previous data indicates that the gene codes for a protein that is expressed in the heads and pharyngeal arches of mouse embryos in developmental stages corresponding to the periods when HFM abnormalities are thought to arise in humans.
Although this is a tantalizing hint as to OTX2’s activity during development, Zielinski cautions that little is known about its overall role, in part because it serves as a transcription factor that regulates other genes.
“OTX2’s activity is very complicated,” says Zielinski, who is first author of the PLOS ONE paper. “Development is dependent on tight control of these transcription factors that turn other genes on and off. The feedback between OTX2 and other transcription factors is complex but we know thatOTX2 plays a critical role in craniofacial patterning.”