The University Record, April 3, 2000

U scientists find genetic mutations associated with epilepsy

By Sally Pobojewski
Health System Public Relations
U-M graduate student Bryan MacDonald (left) loads DNA samples from individuals with epilepsy into a gel electrophoresis device, which separates the DNA molecules. This is the first step in the long process Andrew Escayg (right), a postdoctoral fellow in the U-M Medical School, used to identify mutations in the sodium channel gene SCN1A. Photo by Bob Kalmbach

U-M scientists have found mutations in a sodium channel gene that regulates electrical activity in nerve cells, which may be the cause of one or more types of inherited epilepsy.

In an article published in the April 2000 issue of Nature Genetics, the researchers describe their discovery of two different mutations in a gene called SCN1A found in DNA samples from two families with an inherited form of epilepsy.

If mutations in this gene exist in people with other common hereditary types of epilepsy, genetic testing could identify at-risk infants at birth, when early treatment could help prevent seizures and potential neurological damage, according to Andrew Escayg, a postdoctoral fellow in the Medical School.

Epilepsy is a heterogeneous disease, meaning that multiple genes are involved and environmental factors are important, too. About 1 percent of the world’s population has one of the many varieties of epilepsy.

Escayg initially studied mutations in a related gene in a strain of laboratory mice with seizure disorders. Using recent data from GenBank—an Internet database where scientists in the publicly funded Human Genome Project post their gene sequencing data—Escayg located the genetic coding of the human SCN1A gene. Using DNA samples provided by researchers at European hospitals, Escayg—working with graduate student Bryan MacDonald—found SCN1A mutations in French families with an inherited form of epilepsy called GEFS+ Type 2, or Generalized Epilepsy with Febrile Seizures Plus Type 2.

Like many children under age 6, children with GEFS+ Type 2 have seizures when they run a high fever. Most children stop having febrile seizures as they grow older. But in children with GEFS+ Type 2, seizures continue, even in the absence of fever. As they become more frequent and severe, these seizures may lead to permanent neurological damage.

“We found two mutations in SCN1A that we believe account for GEFS+ Type 2,” Escayg says. “SCN1A is the fifth epilepsy gene found so far. The other four are associated with rare forms of the disease.”

“We think this is just the tip of the iceberg,” says Miriam H. Meisler, professor of human genetics. “Ten percent to 15 percent of adults with epilepsy had recurrent seizures with fever as a child, so mutations in SCN1A may be associated with many varieties of epilepsy. It is a good candidate to test for other neurological disorders as well.”

Expressed widely in the central and peripheral nervous system, SCN1A is the genetic code for a sodium channel found in neurons, according to Meisler. Sodium channels are tiny pores that open to allow positively charged sodium ions to enter the nerve cell and then close to cut off the electrical signal. If the channel doesn’t work properly, the neuron is exposed to abnormal electrical stimulation.

“Sodium channel genes determine the level of excitability in neurons,” Meisler explains. “Epileptic seizures are triggered by overexcited neurons. Since the SCN1A mutations are located in the positively charged parts of the molecule, it suggests they affect the ability of these pores to open or close normally.”

Sodium channels are so essential to life that humans have 10 different genes dedicated to regulating the process—some control the passage of electrical signals in muscle cells, some in cardiac cells and some in neurons. These genes appear to be particularly significant, because they have been maintained throughout long periods of evolutionary development. From fruit flies to human beings, the organization of their DNA building blocks is identical.

In future research, Meisler, Escayg and colleagues hope to identify the functional impact of alterations in SCN1A by developing strains of laboratory mice with each individual mutation. They hope to do the same for SCN8A—another sodium channel gene studied in Meisler’s laboratory. Mice with mutations on the SCN8A gene have several neurological disorders—including lack of muscular coordination, spasms and progressive paralysis.

The research was funded by the National Institutes of Health, the Swiss National Science Foundation and the Association pour le Developpement de la Recherche sur le Maladies Genetiques Neurologiques et Psychiatriques.

Collaborators in the study include Stephanie Baulac, Gilles Huberfeld, Isabelle An-Gourfinkel, Alexis Brice and Eric LeGuern from the Hopital de la Salpetriere in Paris; Bruno Moulard, Catherine Buresi and Alain Malafosse from the Hopitaux Universitaires de Geneve in Chene-Bourg, Switzerland; and Denys Chaigne from the Clinique Sainte-Odile in Strasbourg, France.