Gene-Reading Problem Linked To Lou Gehrig's Disease
BALTIMORE, MD -- March 23, 1998 -- 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," said 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 there were problems in the cutting and
pasting," Rothstein explained. "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 said. 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.
