Columbia Health Sciences researchers have identified a gene implicated in a rare form of epilepsy, a finding that could provide insights into the cause of common epilepsy.
Led by Dr. Ruth Ottman, Columbia investigators identified the gene, called LGI1, by extensively studying five families in which some members had an uncommon type of epilepsy characterized by auditory hallucinations and other symptoms. During a seizure, affected individuals often hear sounds that are not real.
The findings will be published Jan. 28 in the online version of Nature Genetics and in the March issue of the journal. Dr. Ottman is professor of epidemiology in the Mailman School of Public Health and deputy director of research at the Gertrude H. Sergievsky Center.
Researchers have not yet identified the genes associated with most forms of epilepsy, a chronic medical condition that affects at least 2.3 million Americans. People with epilepsy have repeated seizures, caused by temporary changes in the electrical function of the brain, that can affect awareness, movement, and sensation. Scientists study rarer familial forms of the disease to get genetic clues about the more common cases.
"Most people with epilepsy do not have family members who are also affected, but unusual families that have multiple affected people can help scientists find genes associated with the disease," Dr. Ottman says. "Discovery of these genes can tell us a lot about the basic processes that lead to seizures."
Before this study, scientists had found eight genes that predispose people to other rare forms of "idiopathic" epilepsy, or unexplained epilepsy that occurs without other serious neurological problems. But the genes identified before allow chemical signals in and out of brain cells and function differently than LGI1. While the function of LGI1 has yet to be determined, some evidence suggests it plays a role in brain development.
"The discovery that LGI1 causes epilepsy with auditory symptoms points to new avenues for studying the causes of all types of epilepsy," Dr. Ottman says. "The gene seems to play a role in how nerve cells migrate during development and create faulty wiring."
In the study, Dr. Ottman and colleagues looked at the pattern of inheritance of the auditory epilepsy in the families. They collected blood from 108 members of five families and analyzed the DNA from 85 of them. They knew from prior studies of one family that a gene associated with epilepsy with auditory symptoms was on chromosome 10.
But in the Nature Genetics paper, the researchers report identifying the gene by studying the DNA from the first family and four other families and finding mutations in affected individuals. Inheriting a mutated copy of the LGI1 gene does not guarantee getting epilepsy, the researchers found. The disorder will develop in 70 percent of individuals who have mutations in the gene.
LGI1 had been characterized by other scientists doing cancer research. They found that loss of both copies of the LGI1 gene promotes the progression of certain types of brain tumors. Dr. Ottman's research has found no evidence for an increased risk of brain cancer in people carrying a mutant copy of the gene.
Dr. Ottman and her colleagues are now studying how the gene works during brain development and how it may relate to other forms of epilepsy.
- This is one of the largest successful positional cloning projects to date, led by Sergey Kalachikov, associate research scientist at the Columbia Genome Center, and T. Conrad Gilliam, professor of genetics and development and director of the Columbia Genome Center.
- The research was supported by grants from the National Institute of Neurological Diseases and Stroke and by funds from the Columbia Genome Center.
Journal
Nature Genetics