Scientists find gene behind a highly prevalent facial anomaly

May 9, 2014 by Nicole Giese Rura, Whitehead Institute for Biomedical Research

Whitehead Institute scientists have identified a genetic cause of a facial disorder known as hemifacial microsomia (HFM). The researchers find that duplication of the gene OTX2 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."

To find the cause of this family's HFM, Zielinski began by searching for a point mutation, but the five of the study participants held no such mutation in common. Next she looked for sections of the genome that are duplicated. All had an extra copy of one 1.3 megabase pair section of chromosome 14. Duplications this large are frequently detrimental.

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 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 that turn other genes on and off. The feedback between OTX2 and other transcription factors is complex but we know that OTX2 plays a critical role in craniofacial patterning."

Intriguingly, another, darker role of OTX2 was highlighted during the course of the study. The little girl who was this research's main focus was diagnosed with medulloblastoma, a highly malignant tumor originating at the base of the brain in or near the cerebellum. OTX2 is a known oncogene for her subclass of medulloblastoma, confirming that her OTX2 expression is out of line.

"OTX2 is one of the most common genes that is amplified in medulloblastoma," says Erlich. "So first you have this gene that is involved in facial development, and then the same gene is involved in some cases of medulloblastoma. It suggests a very interesting link between the two."

Despite the dim prognosis normally associated with this cancer, the girl has gone through treatment and is currently in remission.

Although an extra copy of OTX2 causes HFM in this family, it is not the only faulty gene responsible for this disorder. Zielinski looked at seven other familial cases of HFM and none had duplication of OTX2, opening up the possibility that there could be several other errant involved in familial HFM.

Explore further: New gene responsible for cleft lip and palate syndrome identified

More information: "OTX2 duplication is implicated in hemifacial microsomia" PLOS ONE, May 9, 2014.

Related Stories

New gene responsible for cleft lip and palate syndrome identified

December 19, 2013
An international team led by researchers from Karolinska Institutet in Sweden has identified a new gene related to the Van der Woude syndrome, the most common syndrome with cleft lip and palate. The study is published in ...

A journey between XX and XY: Researchers get closer to unravelling the mystery of sexual ambiguity

May 5, 2014
A team of researchers from the University of Geneva (UNIGE) has been involved in a thorough genetic investigation based on the case of a child suffering from the Nivelon-Nivelon-Mabille Syndrome, a complex condition characterised ...

Identified epigenetic factors associated with an increased risk of developing cancer

April 10, 2014
In 10% of human tumors there is a family history of hereditary disease associated with mutations in identified genes. The best examples are the cases of polyps in the large intestine associated with the APC gene and breast ...

Scientists ignore cultural barriers to find the cause of a rare disease

April 11, 2011
In a research collaboration blind to affairs of politics, ethnicity, and religion, an international team led by Israeli scientists has identified the genetic cause of a neurological disorder afflicting members of a Palestinian ...

Recommended for you

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

Two new breast cancer genes emerge from Lynch syndrome gene study

January 18, 2018
Researchers at Columbia University Irving Medical Center and NewYork-Presbyterian have identified two new breast cancer genes. Having one of the genes—MSH6 and PMS2—approximately doubles a woman's risk of developing breast ...

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.