Featured Research

from universities, journals, and other organizations

Gene behind highly prevalent facial anomaly found

Date:
May 9, 2014
Source:
Whitehead Institute for Biomedical Research
Summary:
A genetic cause of a facial disorder known as hemifacial microsomia (HFM) has been discovered by scientists. 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 -- until now.

The genetic cause of this girl's hemifacial microsomia (HFM) was the focus of research conducted by Whitehead Institute Fellow Yaniv Erlich and his lab. 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.
Credit: Courtesy of PLOS ONE

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.

Related Articles


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 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 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 genes involved in familial HFM.

This work is supported by the Andria and Paul Heafy Family Fellowship, the Burroughs Wellcome Fund, Cathy and Jim Stone, and Ron Casty.

Written by Nicole Giese Rura

* * *

Yaniv Erlich is the Andria and Paul Heafy Fellow of Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted.

* * *

Full Citation:

"OTX2 duplication is implicated in hemifacial microsomia"

PLOS ONE, May 9, 2014.

Dina Zielinski (1), Barak Markus (1), Mona Sheikh (1), Melissa Gymrek (1,2,3,4), Clement Chu (5), Marta Zaks (6), Balaji Srinivasan (5), Jodi D. Hoffman (7), Dror Aizenbud (6,+), Yaniv Erlich (1,+).

1.Whitehead Institute for Biomedical Research, Cambridge, MA, USA 2. Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA, USA 3. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA 4. Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA 5. Counsyl, South San Francisco, CA, USA 6. Rambam Health Care Campus, Haifa, Israel 7. Division of Genetics, Tufts Medical Center, Boston, MA, USA + Equal contribution


Story Source:

The above story is based on materials provided by Whitehead Institute for Biomedical Research. The original article was written by Nicole Giese Rura. Note: Materials may be edited for content and length.


Journal Reference:

  1. Dina Zielinski, Barak Markus, Mona Sheikh, Melissa Gymrek, Clement Chu, Marta Zaks, Balaji Srinivasan, Jodi D. Hoffman, Dror Aizenbud, Yaniv Erlich. OTX2 Duplication Is Implicated in Hemifacial Microsomia. PLoS ONE, 2014; 9 (5): e96788 DOI: 10.1371/journal.pone.0096788

Cite This Page:

Whitehead Institute for Biomedical Research. "Gene behind highly prevalent facial anomaly found." ScienceDaily. ScienceDaily, 9 May 2014. <www.sciencedaily.com/releases/2014/05/140509172543.htm>.
Whitehead Institute for Biomedical Research. (2014, May 9). Gene behind highly prevalent facial anomaly found. ScienceDaily. Retrieved October 30, 2014 from www.sciencedaily.com/releases/2014/05/140509172543.htm
Whitehead Institute for Biomedical Research. "Gene behind highly prevalent facial anomaly found." ScienceDaily. www.sciencedaily.com/releases/2014/05/140509172543.htm (accessed October 30, 2014).

Share This



More Health & Medicine News

Thursday, October 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Fauci Says Ebola Risk in US "essentially Zero"

Fauci Says Ebola Risk in US "essentially Zero"

AP (Oct. 30, 2014) NIAID Director Anthony Fauci said the risk of Ebola becoming an epidemic in the U.S. is essentially zero Thursday at the Washington Ideas Forum. He also said an Ebola vaccine will be tested in West Africa in the next few months. (Oct. 30) Video provided by AP
Powered by NewsLook.com
Nurse Defies Ebola Quarantine With Bike Ride

Nurse Defies Ebola Quarantine With Bike Ride

AP (Oct. 30, 2014) A nurse who vowed to defy Maine's voluntary quarantine for health care workers who treated Ebola patients followed through on her promise Thursday, leaving her home for an hour-long bike ride. (Oct. 30) Video provided by AP
Powered by NewsLook.com
Microsoft Launches Fitness Band After Accidental Reveal

Microsoft Launches Fitness Band After Accidental Reveal

Newsy (Oct. 30, 2014) Microsoft accidentally revealed its upcoming fitness band on Wednesday, so the company went ahead and announced it. Video provided by Newsy
Powered by NewsLook.com
Bracing to Meet a Killer: Aid Workers Prep for Ebola in Geneva

Bracing to Meet a Killer: Aid Workers Prep for Ebola in Geneva

AFP (Oct. 30, 2014) At the International Federation of Red Cross and Red Crescent Societies, around 30 doctors, nurses, lab technicians and water and sanitation workers are gathered for a crash-course in how to safely deal Ebola. Duration: 01:31 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins