Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

NIH-Funded Study Discovers New Genes for Childhood Epilepsies

Published: Tuesday, August 13, 2013
Last Updated: Tuesday, August 13, 2013
Bookmark and Share
New strategy may find more genes and provide a better understanding of these and other complex neurological disorders.

A genetic study of childhood epilepsies has linked two new genes to severe forms of disease and provides a novel strategy for identifying therapy targets. This study used a cutting-edge genetic technique, called exome sequencing, to search for new mutations that are not inherited. The results suggest this may be a highly effective way to find and confirm many disease-causing gene mutations.

“It appears that the time for using this approach to understand complex neurological disorders has arrived,” said David Goldstein, Ph.D., director of the Center for Human Genome Variation at Duke University Medical Center, Durham, N.C., and a leader of the study. “This moderately-sized study identified an unusually large number of disease-causing mutations and provides a wealth of new information for the epilepsy research community to explore.”

The study is part of a worldwide, $25 million project, largely funded by the National Institutes of Health, called Epilepsy 4000 (Epi4K  ). Epi4K’s mission is to use the latest genetic techniques to sequence and analyze DNA from 4000 epilepsy patients and their relatives. To do this, the researchers and NIH staff involved organized a team of international research institutions devoted to the mission, called the Epilepsy Centers without Walls. This approach facilitates the sharing and analysis of DNA sequences and patient information among the dozens of institutions participating in the project. The study, published in Nature by the Epi4K and Epilepsy Phenome/Genome Project (EPGP) Investigators, found as many as 25 epilepsy-causing mutations in new and previously identified genes.

“These promising results highlight the strength of supporting large international research teams devoted to studying the genetics behind highly complex neurological disorders,” said Story Landis, Ph.D., director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS). The project is also led by Daniel Lowenstein, M.D., a vice chair of the Department of Neurology at the University of California, San Francisco (UCSF) and Sam Berkovic, M.D., director of the Epilepsy Research Center at the University of Melbourne, Australia on behalf of an international team of investigators.

Epilepsy is a group of neurological disorders caused by abnormal firing of nerve cells in the brain which often produces debilitating seizures and a range of other symptoms. More than 2 million people in the United States suffer from epilepsies, and infants and children have a greater chance of having the disorders than adults. Although some studies have found genes associated with rare inherited forms of epilepsy, finding genes associated with the majority of epilepsies has been difficult.

“Unlike some diseases many of the genetic mutations associated with severe childhood epilepsies appear to be new mutations that are not inherited,” said Randall Stewart, Ph.D., a program director at NINDS. “This Epi4K-EPGP project was established to find such mutations.”

In this study, the researchers used exome sequencing to find mutations that might cause two devastating forms of childhood epilepsy, called infantile spasms and Lennox-Gastaut Syndrome. DNA and clinical data were originally collected through the NIH-funded Epilepsy Phenome/Genome Project which was led by Dr. Lowenstein and Elliot Sherr, M.D., Ph.D., director of the Comprehensive Center for Brain Development at UCSF and Dr. Ruben Kuzneicky, M.D., professor at the New York University Comprehensive Epilepsy Center.

“The Epilepsy Phenome/Genome Project, with its massive data set, laid the groundwork for this study, and the key to this success has been the extraordinary level of collaboration among more than 115 investigators, study coordinators and administrative personnel involved in both EPGP and Epi4K,” said Dr. Lowenstein.

Exomes essentially represent all of a person’s genes. Their DNA sequences provide the instructions for constructing all the proteins made by the body. The researchers compared exome sequences of 264 children with the sequences of their parents who do not have epilepsy. Differences in the sequences of these subject trios were analyzed using a number of statistical tools to identify potential disease causing mutations. Compared with some genetic studies, this research sequenced DNA from relatively few patients. Nonetheless, the researchers were able to find disease-causing mutations in six genes: four had been described before using other genetic techniques and two genes are implicated for the first time.

Using novel genetic analysis techniques, the researchers also demonstrated that epilepsy-causing mutations are concentrated in genes that are highly sensitive, or intolerant, to changes in their DNA sequence in human populations. These genes are so sensitive that even the slightest change can cause the gene not to work, leading to death or severe forms of diseases.

“This study used a very sophisticated bioinformatics approach to analyze DNA sequences and find disease-causing mutations,” said Katrina Gwinn, M.D., a program director at NINDS.

To find more genes that are likely to have epilepsy-causing mutations, the researchers searched thousands of exome sequences from healthy volunteers who participated in the National Heart Lung and Blood Institute Exome Sequencing Project. They looked for gene sequences that had only slight differences among subjects because previous studies showed that these sequences are highly sensitive to mutations. The researchers estimated that up to 90 genes could carry epilepsy-causing mutations and that many of the mutations implicated in the risk of epilepsy have been previously associated with other neurodevelopmental diseases, including autism.

“One of the most encouraging aspects of this study is that we’re beginning to see how best to interpret and make effective use of exome sequence data,” said Dr. Goldstein. “We anticipate that further studies will identify many new disease-causing genes and we intend to develop a watch list of the genes which summarizes their clinical characteristics in way that will be helpful for doctors, patients, and researchers.”

For instance, the researchers analyzed how the genes that could carry epilepsy-causing mutations work and interact. Their analysis showed that the genes can be grouped into a few networks. Each network appears to play an important role in the growth and development of a child’s nervous system.

“It appears that a few pathways may be responsible for many severe pediatric epilepsies,” said Dr. Goldstein, “If true, then understanding epilepsies will be more manageable and we can find common pathways to target with drugs and other therapies.”


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 2,500+ scientific posters on ePosters
  • More than 3,700+ 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 TechnologyNetworks.com 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

NIH Scientists Visualize how Cancer Chromosome Abnormalities form in Living Cells
For the first time, scientists have directly observed events that lead to the formation of a chromosome abnormality that is often found in cancer cells.
Friday, August 09, 2013
NIH Adds First Images to Major Research Database
More than 72,000 clinical photographs illustrate age-related eye disease progression.
Tuesday, November 23, 2010
Genetic Study Confirms the Immune System's Role in Narcolepsy
Scientists identify a gene associated with narcolepsy which suggests that autoimmunity plays an important role in the disorder.
Wednesday, May 06, 2009
Skin Cancer Study Uncovers a New Tumor Suppressor Gene
Genetic analysis of a key group of enzymes may pave the way for more individualized treatments.
Monday, March 30, 2009
Alcohol Flush Signals Increased Cancer Risk Among East Asians
Many people of East Asian descent possess an enzyme deficiency that causes their skin to redden, or flush, when they drink alcohol.
Tuesday, March 24, 2009
Researchers Develop DNA "Patch" for Canine form of Muscular Dystrophy
This finding lays the foundation for human testing.
Friday, March 20, 2009
Scientists Identify Gene Variant Involved in Isolated Cleft Lip
About 20 percent of isolated cleft lip, one of the world's most common birth defects, may be due to a one-letter difference in the DNA sequence of a gene involved in facial development, researchers supported by the National Institutes of Health report.
Monday, October 06, 2008
NIH Funds Nine Centers to Speed Application of Powerful New Research Approach
The funding of a network of nine centers across the country that will use high tech screening methods to identify small molecules for use as probes to investigate the diverse functions of cells was announced today by the National Institutes of Health (NIH).
Wednesday, September 03, 2008
Scientific News
Liquid Biopsies: Utilization of Circulating Biomarkers for Minimally Invasive Diagnostics Development
Market Trends in Biofluid-based Liquid Biopsies: Deploying Circulating Biomarkers in the Clinic. Enal Razvi, Ph.D., Managing Director, Select Biosciences, Inc.
Watching a Tumour Grow in Real-Time
Researchers from the University of Freiburg have gained new insight into the phases of breast cancer growth.
Childhood Cancer Cells Drain Immune System’s Batteries
Cancer cells in neuroblastoma contain a molecule that breaks down a key energy source for the body’s immune cells, leaving them too physically drained to fight the disease.
Urine Proteins Point to Early-Stage Pancreatic Cancer
A combination of three proteins found at high levels in urine can accurately detect early-stage pancreatic cancer, researchers at the BCI have shown.
Researcher Discovers Trigger of Deadly Melanoma
New research sheds light on the precise trigger that causes melanoma cancer cells to transform from non-invasive cells to invasive killer agents, pinpointing the precise place in the process where "traveling" cancer turns lethal.
Genetic Tug of War
Researchers have reported on a version of genetic parental control in mice that is more targeted, and subtle than canonical imprinting.
Error Correction Mechanism in Cell Division
Cell biologists have reported an advance in understanding the workings of an error correction mechanism that helps cells detect and correct mistakes in cell division early enough to prevent chromosome mis-segregation and aneuploidy, that is, having too many or too few chromosomes.
How to Become a Follicular T Helper Cell
Uncovering the signals that govern the fate of T helper cells is a big step toward improved vaccine design.
Researchers Resurrect Ancient Viruses
Researchers at Massachusetts Eye and Ear and Schepens Eye Research Institute have reconstructed an ancient virus that is highly effective at delivering gene therapies to the liver, muscle, and retina.
Cell Aging Slowed by Putting Brakes on Noisy Transcription
Experiments in yeast hint at ways to extend life of some human cells.
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
2,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!