Gene ‘typo’ explains severe epilepsy

U. ARIZONA (US) — A previously unknown mutation in a sodium channel protein likely causes a severe form of epilepsy.

A team headed by Michael Hammer at the University of Arizona applied Next Generation Genome Sequencing to decipher the entire DNA from a patient who suffered a sudden unexplained epileptic death.

They found the likely culprit—a previously unknown mutation in a gene coding for a sodium channel protein in the central nervous system—and their findings offer some emotional relief and explanation to the patient’s family in the absence of a medical diagnosis and any family history of similar disease. The research team’s results appear in the American Journal of Human Genetics.

“If you have a small child with severe epilepsy, not knowing what is causing it is a big burden to carry for the family,” says Michael Hammer, an associate professor in the department of ecology and evolutionary biology. “It leaves a lot of open questions and sometimes even feelings of guilt.”



“We were tasked with the search for the proverbial needle in a haystack,” says Veeramah, a postdoctoral fellow in Hammer’s lab. “To find a de novo mutation, we have to comb through the entire genome. In the old days, we could have generated a list of candidate genes and sequenced them one gene at a time.

“Unfortunately that’s a lot of work, especially in the brain where you have thousands of genes that could potentially be involved in a process leading to a neurological disorder. The development of Next Generation Sequencing Technology in recent years provides a much more powerful approach to actually analyze all the genes at the same time. So that’s what we wanted to do.

“We are looking at the level of the entire genome,” Hammer adds, “something that was not possible until very recently. For a neurological disorder like this, the cause could be a mutation in a particular gene; it could be a certain sequence that was rearranged; or it could be a sequence that was deleted or duplicated changing the number of gene copies.

“We all have variations in the number of copies of certain genes, but they’re not necessarily bad,” he explains. “But sometimes that variation can cause disease. For example, some percentage of previously unexplained intellectual disability has been found to be associated with genomic rearrangements.”

Avoiding errors

In this case, the researchers did not find a smoking gun from looking at copy number variations, which left point mutations or small insertions or deletions of DNA letters as a likely cause.






They hoped that somewhere in that pool of candidates was that one mutation that had caused the girl’s epilepsy and possibly led to her death.


“De novo mutations will look like they don’t obey the rules by which we know genetic material is inherited,” Veeramah explains. “The patient will have a variant that is not found in the parents or the sibling. We found 34 sites that fit this pattern.”





Mutation’s consequences




“When the voltage is increased, there is a sudden opening of sodium channels,” Veeramah says. “Shortly afterward, they close really quickly and the voltage goes back to normal. And that’s essentially how normal neurons communicate, how electrical signals are sent around the brain and the body.”

“In contrast, the mutant channel proteins opened as quickly as they should, but some of them failed to close quickly, and some didn’t close at all,” Veeramah explains. “All this results in the electrical signal not being turned off properly. These changes predicted increased neuronal excitability and seizures.”



“We want to repeat this experiment with many more patients,” Hammer says. “We are ready to accept DNA from patients and carry out this type of study.”

Veeramah adds: “Right now we are doing basic research to identify all the mutations involved. Down the line the goal is to design drugs that specifically target the affected pathways.”





More news from the University of Arizona:

chat2 Comments



  1. Katy Seybold

    I just came upon this site. I have many questions about epilepsy. My brother was afflicted and passed last week. His seizures were so severe and he seemed to have many types. He was 59 when he passed after spending almost 9 years in a convalescent home which I believe over medicated him.

    I wanted to get genetic coding done to determine whether this was hereditary or not. Please advise me on what type of sample to collect. Time is of the essence. Do I need blood, hair, sliva swab or ??? Where should I have the testing done. Is it genetic coding or profiling which I need? It may be hereditary. My parents, sister (and her children), and myself (and my children) do not seem to be afflicted. There may be occurances on my fathers side.
    Thank you,

  2. Bailey

    Superb blog and fantastic design.

We respect your privacy.