First Common Genetic Mutations Found In Sporadic ALS Patients

November 22, 1996

Johns Hopkins researchers have identified two genetic mutations that appear to cause or contribute to nearly half of all non-inherited cases of the deadly muscle disease amyotrophic lateral sclerosis (ALS), or Lou Gehrig's Disease.

"For the first time we've identified mutations that occur widely in sporadic cases of ALS," says Jeffrey Rothstein, M.D., Ph.D., associate professor of neurology. "This may ultimately help us speed up diagnosis of ALS and improve treatments--all the things we're going to be working on over the years."

Rothstein, postdoctoral fellow Glen Lin, Ph.D., and research associate Lynn Bristol, Ph.D., are scheduled to present their data at the annual meeting of the Society for Neuroscience this week in Washington, D.C. (Note embargo.)

The mutations involve a glutamate transporter protein, EAAT2, which normally deactivates and recycles glutamate, a chemical nerve cells use to send messages to each other.

Hopkins researchers had previously shown that many ALS patients have little or no EAAT2 protein in certain areas of the brain and spinal cord, creating an excess of glutamate that kills the nerves that control muscles.

The usual result is gradually increasing paralysis and death in two to five years. Nearly 30,000 people currently have the disease; 95 percent of them are thought to be sporadic or non-inherited.

The first step in the Hopkins study was analysis of the genes of a familial (inherited) ALS patient with an unusually widespread loss of EAAT2. They found the patient's EAAT2 gene was not translated properly into a decoded form of the gene known as RNA. Like a computer removing bad program lines, a cell's machinery is supposed to cut out inactive pieces of genetic material, or introns, and link the active pieces, or exons, to assemble the RNA "blueprint" it uses to make a protein.

"In this patient, some introns were kept while an exon was discarded, producing defective RNA," Rothstein says.

Next, researchers searched for and found the same mutation in 42 percent of ALS patients they surveyed. In many patients, they also found a slightly different error: an RNA copy of the EAAT2 gene where all of the introns were removed, but an essential exon was also removed.

In lab experiments, the bad RNA either produced a useless version of EAAT2 or suppressed production of normal EAAT2.

Scientists could not find either mutation in brain tissue from 12 normal subjects or 16 patients with Huntington's Disease, Alzheimer's Disease, or spinal muscular atrophy, an inherited disorder similar to ALS.

"We've just started working on it, but if these mutations really are specific to ALS and we can develop a test to detect them, that could help us make the diagnosis and begin treatment much earlier in the course of the disease," he explains.

Rothstein and others are also looking at possible causes of the mutations.

"We've linked the mutations to ALS symptoms pretty firmly, but we still don't know if they are a primary cause of ALS or the result of another problem," he says.

Something may go wrong in the biochemical machinery the body uses to decode the EAAT2 gene, Rothstein explains. It's also possible that there is an acquired or inherited mutation in the introns of EAAT2 that gives this machinery the wrong cues, fouling up the decoding process.

The new finding is among the first to be partially funded by the Cal Ripken/Lou Gehrig Fund for Neuromuscular Research, a fund for research into ALS and other neuromuscular diseases created in 1995 when Ripken broke Gehrig's longstanding record for consecutive games played.

Other funding organizations included the National Institutes of Health, the Muscular Dystrophy Association, and the ALS Association.

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Johns Hopkins Medicine

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