Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Mass. General, Duke Study Identifies Two Genes that Combine to Cause Rare Syndrome

Published: Monday, May 13, 2013
Last Updated: Monday, May 13, 2013
Bookmark and Share
Mutations in genes that regulate cellular metabolism found in families with ataxia, dementia and reproductive failure.

Researchers from Massachusetts General Hospital (MGH) and Duke University have identified genetic mutations that appear to underlie a rare but devastating syndrome combining reproductive failure with cerebellar ataxia – a lack of muscle coordination – and dementia.  In a paper that will appear in the May 23 New England Journal of Medicine and is receiving early online release, the investigators describe finding mutations in one or both of two genes involved in a cellular process called ubiquitination in affected members of five unrelated families.

"This study highlights, for the first time, the importance of the ubiquitin system in a syndrome characterized by ataxia and hypogonadotropic hypogonadism – reproductive failure due to abnormal signaling from the brain or pituitary gland," says Stephanie Seminara, MD, of the Reproductive Endocrine Unit in the MGH Department of Medicine, co-senior author of the report.  "It also demonstrates how combining robust genomics with detailed functional assays can unlock complex genetic architecture."

Caused by lesions in the part of the brain responsible for coordination and balance, cerebellar ataxia can begin with difficulty walking or speaking and progress to complete disability of those functions.  Genes associated with several syndromes characterized by ataxia have been identified, but none had previously been associated with the rare combination of ataxia and reproductive failure, which was first described more than 100 years ago.  Several such patients have been referred to the MGH Reproductive Endocrine Unit, including a Palestinian family with several affected members who also developed dementia.

Seminara notes that, while ataxia and hypogonadotropic hypogonadism each may have several possible genetic causes, the combination of both conditions is so rare that it is more likely to be caused by mutations in a particular gene or related genes.  In collaboration with researchers from the Center for Human Disease Modeling at Duke – directed by Nicholas Katsanis, PhD, co-senior author of the NEJM article – her team conducted whole-exome sequencing of DNA from an affected member of the Palestinian family.  That screening found rare variants in both copies of 13 genes, and two of those variants were also found in samples from the patient's two affected siblings but not in several unaffected family members.

Both of the mutated genes are involved in ubiquitination, a process by which cellular proteins are marked for degredation by a protein called ubiquitin.  One of them, RNF216, codes for an enzyme that attaches ubiquitin to the protein; the other, OTUD4, codes for a protein that removes ubiquitin.  The researchers then sequenced both of these proteins in samples from an additional nine affected individuals from seven different families.  They found that one of those individuals had two different RNF216 mutations, four others – two in the same family – had mutations in a single copy of that gene, but none had mutated versions of OTUD4.

All of the individuals with RNF216 mutations had similar medical histories, characterized by a lack of normal hormonal secretion, progressive ataxia and dementia; and all of those with mutations in both genes died in their 30s or 40s.  Neuroimaging studies revealed similar brain abnormalities – including atrophy of the cerebellum and cortex – in individuals with RNF216 mutations.  The four studied individuals without RNF216 mutations had very different histories, with less severe symptoms.

To get a better idea of the functional consequences of mutations in these two genes, the researchers disrupted their expression in zebrafish and found that blocking either RNF216 or OTUD4 caused disorganization of the cerebellum and reduced the size of eyes and a portion of the midbrain.  The abnormalities were even greater when both genes were blocked but could be eliminated if production of the relevant proteins was induced by the introduction of the corresponding human RNA.

"The presence of RNF216 mutations in several familes made its role in causing this syndrome clear, but finding OTUD4 mutation in only one family raised the question of whether it actually contributed to the disease or was just an 'innocent bystander'," says Katsanis.  "The zebrafish work provided critical evidence that both genes function in a common pathway, since blocking either of them produced similar effects.  And the fact that blocking both genes had a synergistic effect lends further evidence to the two genes' operating in the same pathway and to the contribution of OTUD4 mutations to this syndrome."

Although exactly how these mutations lead to the symptoms seen in these individuals is unknown, the researchers note that identifying these genes may someday lead to therapies – potentially including drugs currently being developed for other disorders involving ubiquitination, including Parkinson's disease – and enable genetic screening and counseling for affected families.  They also hope to investigate whether less severe mutations in these genes may contribute to the presence of ataxia, dementia or hypogonadism in isolation.

Seminara is an assistant professor of Medicine at Harvard Medical School, and Katsanis is the Jean and George W. Brumley Professor of Cell Biology and Pediatrics at Duke University Medical Center. The co-lead authors of the NEJM report are David Margolin, MD, PhD, MGH Department of Neurology; Maria Kousi, PhD, Duke Center for Human Disease Modeling; and Yee-Ming Chan, MD, PhD, MGH Reproductive Endocrine Unit and Boston Children's Hospital. The study was supported by National Institute for Child Health and Human Development grants R01 HD043341, R01 HD042601 and U54 HD028138 and by other National Institutes of Health grants.

Duke Medicine encompasses the Duke University Health System, the Duke University School of Medicine, and the Duke University School of Nursing. Its mission is to serve as a world-class academic and health care system, working to transform medicine and health locally and globally through innovative scientific research, rapid translation of breakthrough discoveries, education of future clinical and scientific leaders and the highest quality of medical practice in the community and beyond.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of "America's Best Hospitals."

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,600+ scientific posters on ePosters
  • More Than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

First Gene that Causes Mitral Valve Prolapse Identified
An international research collaboration led by MGH investigators has identified the first gene in which mutations cause the common form of mitral valve prolapse, a heart valve disorder that affects almost 2.5 percent of the population.
Tuesday, August 11, 2015
Intracellular Microlasers Could Allow Precise Labeling of up to a Trillion Individual Cells
MGH investigators have induced structures incorporated within individual cells to produce laser light at wavelengths that differ based on the size, shape and composition of each microlaser, allowing precise labeling of individual cells.
Tuesday, August 04, 2015
Evo-Engineered CRISPR-Cas9s Hit More Gene-Editing Targets
Scientists have engineered a more effective CRISPR- Cas9 system paving the way for more advanced applications.
Wednesday, June 24, 2015
Reducing Chemotherapy Drug’s Cardiac Side Effects
Preventing doxorubicin-induced cardiotoxicity could improve chemotherapy outcomes, reduce heart failure risk.
Thursday, December 11, 2014
Direct Drug Screening Of Biopsies Could Overcome Resistance
Combining genetic with pharmacologic screening of tumors may enable truly individualized treatment regimens.
Monday, November 17, 2014
Culture System Replicates Course Of Alzheimer’s Disease
Three-dimensional system should significantly reduce time and costs of drug development.
Monday, October 20, 2014
Genetic Signals Reflect the Evolutionary Impact of Cholera
Study identifies regions of genome associated with cholera susceptibility in Bangladesh.
Monday, July 08, 2013
Powerful Gene-Editing Tool Appears to Cause Off-Target Mutations in Human Cells
Results indicate need to improve precision of CRISPR-Cas RNA-guided nucleases.
Wednesday, June 26, 2013
Phase 1 ALS Trial is First to Test Antisense Treatment of Neurodegenerative Disease
No serious adverse effects seem from central-nervous-system infusion of drug that blocks mutated protein.
Tuesday, April 09, 2013
Protein Controlling Glucose Metabolism also a Tumor Suppressor
A protein known to regulate how cells process glucose also appears to be a tumor suppressor, adding to the potential that therapies directed at cellular metabolism may help suppress tumor growth.
Tuesday, December 11, 2012
Detection, Analysis of 'Cell Dust' may Allow Diagnosis, Monitoring of Brain Cancer
System combining nanotechnology and NMR detects particles shed by brain tumors in bloodstream.
Thursday, November 15, 2012
Circulating Tumor Cells can Reveal Genetic Signature of Dangerous Lung Cancers
MGH-developed device promises improvements in targeted therapy, treatment monitoring.
Friday, July 04, 2008
Gene Variation may Elevate Risk of Liver Tumor in Patients with Cirrhosis
A single alteration in the epidermal growth factor (EFG) gene may greatly increase the risk of developing hepatocellular carcinoma, researchers say.
Tuesday, January 08, 2008
Scientific News
Fixing Holes in the Heart Without Invasive Surgery
UV-light enabled catheter is a medical device which represents a major shift in how cardiac defects are repaired.
Chromosomal Chaos
Penn study forms basis for future precision medicine approaches for Sezary syndrome
Enzyme Malfunction May be Why Binge Drinking Can Lead to Alcoholism
A new study in mice shows that restoring the synthesis of a key brain chemical tied to inhibiting addictive behavior may help prevent alcohol cravings following binge drinking.
Key to Natural Detoxifier’s Reactivity Discovered
Results have implications for health, drug design and chemical synthesis.
New Treatment for Obesity Developed
Researchers at the University of Liverpool, working with a global healthcare company, have helped develop a new treatment for obesity.
New Protein Found in Immune Cells
Immunobiologists from the University of Freiburg discover Kidins220/ARMS in B cells and demonstrate its functions.
Will Brain Palpation Soon Be Possible?
Researchers have developed non-invasive brain imaging technique which provides the same information as physical palpation.
Shaking Up the Foundations of Epigenetics
Researchers at the Centre for Genomic Regulation (CRG) and the University of Barcelona (UB) published a study that challenges some of the current beliefs about epigenetics.
Groundbreaking Computer Program Diagnoses Cancer in Two Days
Researchers have combined genetics with computer science and created a new diagnostic technology can with 85 per cent certainty identify the source of the disease and thus target treatment and, ultimately, improve the prognosis for the patient.
Michigan Researchers Use Raman Spectroscopy
inVia confocal Raman microscope used in the study of various childhood diseases.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos