Featured Research

from universities, journals, and other organizations

New Epilepsy Gene Identified In Mice

Date:
August 30, 2001
Source:
Howard Hughes Medical Institute
Summary:
Researchers have identified a novel gene that is mutated in mice that develop spontaneous epileptic seizures in response to loud noises. The brain protein affected by the mutation is unlike any other known to cause epilepsy in mice or humans.

Researchers have identified a novel gene that is mutated in mice that develop spontaneous epileptic seizures in response to loud noises. The brain protein affected by the mutation is unlike any other known to cause epilepsy in mice or humans.

In an article published in the August 30, 2001, issue of the journal Neuron, a research team led by Howard Hughes Medical Institute investigator Louis J. Ptacek at the University of Utah reported cloning and sequencing the gene that is responsible for an audiogenic form of reflex epilepsy in the Frings mouse strain. Although this mouse strain -- in which seizures can be triggered by a loud noise -- has been used in research for half a century, the genetic defect underlying the disorder had been unknown.

"The Frings mouse shows a form of audiogenic reflex epilepsy precipitated by sound. This is a common form of epilepsy in mice and is similar to the human reflex epilepsies triggered by stimuli such as strobe lights," said Ptacek. "Since the same antiepileptic drugs that work in other forms of epilepsy also work in this form, we are hoping that this will be a generalizable and useful model of epilepsy."

In earlier work, Ptacek and his colleagues narrowed the search for the Frings defect to a region of DNA, or locus, on mouse chromosome 13. Compared to other mouse models of audiogenic epilepsy, where mutations were thought to reside at multiple loci, the Frings mice appeared to be unusual because their mutation was in a single locus.

After narrowing their search, Ptacek and his colleagues then set out to map this locus finely enough to identify the specific causative gene. "It was just a matter of brute force, in which we generated a colony of twelve hundred mice and performed genotyping on them to home in on the gene," said Ptacek.

"Eventually, we localized the gene to precisely thirty six thousand base pairs and just sequenced that whole region." DNA sequencing showed that only one gene lay within the locus, said Ptacek. And within that gene, Ptacek and his colleagues found a single deletion of a DNA base pair that created a stop signal that truncated the normal protein, and rendered it nonfunctional. The scientist named the gene mass1, for "monogenic audiogenic seizure-susceptible."

"We did encounter one fascinating twist that complicated things," said Ptacek. "In comparing other mouse strains closely related to Frings, we found one that had many of the same genetic polymorphisms, but not the deletion. However another strain, called BUB/BnJ, did have the same deletion but was not known to suffer audiogenic seizures. So, we thought we might have a serious problem in demonstrating that this deletion caused epilepsy."

The scientists found that due to hearing loss, these mice lose their susceptibility to seizure during maturation and, thus, would not respond to seizure-inducing sound. When the researchers tested young BUB/BnJ mice, all of them showed such seizures. This finding, said Ptacek, demonstrated clearly that the mass1 gene mutation caused audiogenic epilepsy.

Analysis of the MASS1 protein structure revealed that it did not resemble any known proteins, particularly ion channels that are known to malfunction in other forms of epilepsy. However, said Ptacek, the protein has multiple regions that resemble those of calcium-binding proteins, suggesting a possible role in regulating calcium flow in neurons.

"We're at the early stages of studying the protein and where it is found, and it has been a very difficult problem," said Ptacek. "An interesting complication is that the messenger RNA that is encoded by the mass1 gene is so low in quantity in the mouse that it is undetectable."

Ptacek and his colleagues were unable to detect the gene initially by the usual technique of creating a library of complementary DNA to the cell's messenger RNA and searching that library. The paucity of messenger RNA (mRNA) could be due to a number of factors, said Ptacek. "It may be that that the cell needs only small amounts of MASS1 protein or that it is highly stable and doesn't need to be produced in great amounts," he said. Another theory is that MASS1 mRNA might rapidly degrade or might be present only during embryonic brain development to wire brain circuitry properly.

The scientists are now developing antibodies to the MASS1 protein to use in tracing its location and interactions with other proteins. The scientists have also identified the human gene homologous to mass1, said Ptacek. In addition, they are collaborating with other scientists who have identified a family whose epilepsy appears to be caused by a mutation at the same locus as the human mass1 gene. The researchers hope to be able to determine whether human MASS1 is the cause of this epilepsy.

"We believe that this protein represents an exciting opportunity to understand a completely different mechanism of epilepsy," he said. "The protein could potentially be a novel therapeutic target, since all of the current anti-convulsant medications act against ion channels. And although these medications work very well on many kinds epilepsy there are still many patients whose epilepsy does not respond to them."


Story Source:

The above story is based on materials provided by Howard Hughes Medical Institute. Note: Materials may be edited for content and length.


Cite This Page:

Howard Hughes Medical Institute. "New Epilepsy Gene Identified In Mice." ScienceDaily. ScienceDaily, 30 August 2001. <www.sciencedaily.com/releases/2001/08/010830081051.htm>.
Howard Hughes Medical Institute. (2001, August 30). New Epilepsy Gene Identified In Mice. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2001/08/010830081051.htm
Howard Hughes Medical Institute. "New Epilepsy Gene Identified In Mice." ScienceDaily. www.sciencedaily.com/releases/2001/08/010830081051.htm (accessed July 30, 2014).

Share This




More Health & Medicine News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Generics Eat Into Pfizer's Sales

Generics Eat Into Pfizer's Sales

Reuters - Business Video Online (July 29, 2014) Pfizer, the world's largest drug maker, cut full-year revenue forecasts because generics could cut into sales of its anti-arthritis drug, Celebrex. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Nigeria Ups Ebola Stakes on 1st Death

Nigeria Ups Ebola Stakes on 1st Death

Reuters - Business Video Online (July 29, 2014) Nigerian authorities have shut and quarantined a Lagos hospital where a Liberian man died of the Ebola virus, the first recorded case of the highly-infectious disease in Africa's most populous economy. David Pollard reports Video provided by Reuters
Powered by NewsLook.com
Running 5 Minutes A Day Might Add Years To Your Life

Running 5 Minutes A Day Might Add Years To Your Life

Newsy (July 29, 2014) According to a new study, just five minutes of running or jogging a day could add years to your life. Video provided by Newsy
Powered by NewsLook.com
Ebola Outbreak Poses Little Threat To U.S.: CDC

Ebola Outbreak Poses Little Threat To U.S.: CDC

Newsy (July 29, 2014) The Ebola outbreak in West Africa poses little threat to Americans, according to officials with the Centers for Disease Control and Prevention. Video provided by Newsy
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:
from the past week

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