Gene-Reading Problem Linked To Lou Gehrig's Disease

March 21, 1998

Problem Occurs In 65 Percent Of Spontaneous ALS Patients

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

"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," says Jeffrey Rothstein, M.D., Ph.D., associate professor of neurology.

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

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

This usually leads to paralysis and death in two to five years. Nearly 30,000 people currently have the disease, and 95 percent of them are thought to have the sporadic form.

The Hopkins team first found evidence of the mutation in a patient who had the inherited form of ALS and unusually reduced levels of EAAT2. The problem, the researchers discovered, was an error in the way the patient's nerve cells were translating the DNA code for EAAT2 into RNA.

Cells use RNA as the blueprint for building a protein. As they translate DNA into RNA, they normally cut out useless bits of DNA called introns and paste together the active parts, called exons. If the introns are not properly removed, they disrupt the blueprint and prevent the cell from making the protein properly.

"In this patient," Rothstein explains, "there were problems in the cutting and pasting. Some of the useless introns in the EAAT2 gene were being kept, while an exon was discarded. That produced defective RNA that led to a defective EAAT2 protein or no protein at all."

The team searched for and found similar mutations in 65 percent of ALS patients they surveyed. The bad RNA either produced a useless version of EAAT2 or suppressed production of normal EAAT2.

When researchers studied where the mutated EAAT2 RNA was present in the body, they found it only in areas where motor nerve cells were dying: in the spine and muscle control areas in the brain.

Scientists could not find the mutations 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.

Rothstein's group next looked for a cause of the RNA problems and unexpectedly found that when the cells translated the genetic material, they cut and pasted randomly instead of at specific spots.

Something may be wrong in the biochemical machinery the body uses to decode the EAAT2 gene, Rothstein speculates.

It's also possible that there is an acquired or inherited mutation in the introns of EAAT2 that gives the wrong cues during the editing process, Rothstein says.

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.

Media contact: Michael Purdy (410) 955-8725
Johns Hopkins Medical Institutions' news releases are available on a PRE-EMBARGOED basis on EurekAlert at, Newswise at and from the Office of Communications and Public Affairs' direct e-mail news release service. To enroll, call 410-955-4288 or send e-mail to or

On a POST-EMBARGOED basis find them at, Quadnet at, ScienceDaily at or on CompuServe in the SciNews-MedNews library of the Journalism Forum under file extension ".JHM".

Johns Hopkins Medicine

Related Nerve Cells Articles from Brightsurf:

Nerve cells let others "listen in"
How many ''listeners'' a nerve cell has in the brain is strictly regulated.

Nerve cells with energy saving program
Thanks to a metabolic adjustment, the cells can remain functional despite damage to the mitochondria.

Why developing nerve cells can take a wrong turn
Loss of ubiquitin-conjugating enzyme leads to impediment in growth of nerve cells / Link found between cellular machineries of protein degradation and regulation of the epigenetic landscape in human embryonic stem cells

Unique fingerprint: What makes nerve cells unmistakable?
Protein variations that result from the process of alternative splicing control the identity and function of nerve cells in the brain.

Ragweed compounds could protect nerve cells from Alzheimer's
As spring arrives in the northern hemisphere, many people are cursing ragweed, a primary culprit in seasonal allergies.

Fooling nerve cells into acting normal
In a new study, scientists at the University of Missouri have discovered that a neuron's own electrical signal, or voltage, can indicate whether the neuron is functioning normally.

How nerve cells control misfolded proteins
Researchers have identified a protein complex that marks misfolded proteins, stops them from interacting with other proteins in the cell and directs them towards disposal.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Research confirms nerve cells made from skin cells are a valid lab model for studying disease
Researchers from the Salk Institute, along with collaborators at Stanford University and Baylor College of Medicine, have shown that cells from mice that have been induced to grow into nerve cells using a previously published method have molecular signatures matching neurons that developed naturally in the brain.

Bees can count with just four nerve cells in their brains
Bees can solve seemingly clever counting tasks with very small numbers of nerve cells in their brains, according to researchers at Queen Mary University of London.

Read More: Nerve Cells News and Nerve Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to