SCIENTISTS HAVE IDENTIFIED GENE THAT MAY RAISE SCHIZOPHRENIA RISK
UC Irvine scientists have identified
a gene that they believe
increases the risk of both schizophrenia and manic-depressive
illness--mental disorders that, combined, affect as many as 5 million
Americans.
Although the history of attempts to associate genes with mental illness
is littered with claimed links that could not be verified, the new
finding
seems credible, some experts said. They noted that the mutated gene
falls into the same class of mutations as recently discovered genes
linked to Huntington's disease, fragile X syndrome and several other
disorders of the brain.
UC Irvine geneticist Jay Gargus is scheduled to report today at a
Baltimore meeting of the American Society for Human Genetics that
the newly identified gene contains an unstable stretch of DNA that
grows longer when the gene is passed from parent to child, increasing
the severity of the disease and decreasing the age of onset--a
hallmark of the new family of genes.
"If our results are confirmed by further studies, this discovery could
lead to the development of new tests to identify those at risk for
these
diseases, and possibly to a new generation of highly targeted drugs
with which to treat them, " he said.
But Gargus cautioned that the new gene is only one of several whose
products combine with environmental factors to produce the
disorders, and its presence in the brain is neither necessary nor
sufficient to cause the disease.
Even so, if the finding is confirmed, it "will provide a window into
the
cause of these very complicated illnesses, " said Dr. Edward Ginns
of
the National Institute of Mental Health. "It's very exciting, " he
said,
but the results need to be validated in a much larger study.
Schizophrenia is a complex mixture of behaviors that include
hallucinations and delusions, problems relating to other people, flat
or
inappropriate emotional expression, bizarre behavior, paranoia and
suspiciousness. Many researchers believe that the disorder is a set
of
loosely related diseases that have been mistakenly lumped under one
name.
Researchers have long suspected a genetic role in the disease. The
odds of developing schizophrenia at some time during an individual's
life are one in 100 but, if a person has a relative with the disorder,
the
odds are 1 in 10. If both parents have it, the odds are 2 in 5, and
if an
identical twin has it, the odds climb to 1 in 2.
In January, researchers from the University of Colorado found one
gene that increases a person's risk of schizophrenia. That gene is
the
blueprint for a receptor that also binds to nicotine, and helps explain
why many schizophrenics smoke heavily. Today's announcement
would mark the second gene linked to the disease.
The new finding is based on the earlier discovery that Huntington's
and at least five other brain disorders are caused by an unstable
segment of DNA. The healthy gene contains a segment in which three
nucleotides--the building blocks of genes--called C, A and G are
repeated a few times.
In Huntington's and the other disorders, genes from the affected
individuals contain a much higher number of C-A-G repeats, and this
somehow changes the function of the proteins produced from the
gene, causing illness.
The mutated genes also show a phenomenon called "anticipation. "
When the gene is passed from parent to child, the number of C-A-G
repeats increases and the disease appears earlier in life. It also
becomes more severe.
Because some families with schizophrenia seem to demonstrate
anticipation, researchers have suspected that it might be caused by
a
similar mutation.
Geneticist Michael O'Donovan of the University of Cardiff in Wales
examined DNA from the blood of schizophrenics and found that it
contained segments with larger numbers of C-A-G repeats than were
in DNA from healthy individuals. But he could not tie the repeats to
a
specific gene.
Meanwhile, working on a completely different project, UC Irvine
physiologist George Chandy was looking through computerized gene
databases for the human counterpart of a newly discovered rat gene.
The gene he was looking for serves as a blueprint for a protein that
allows potassium ions to pass through cellular membranes.
He found the gene and noted that it contained previously
unrecognized C-A-G repeats. "It was a fortuitous finding because we
don't normally work on neural genes, " said his collaborator,
geneticist George Gutman.
Especially promising was the fact that the gene, called hSKCa3, was
in a narrow region of chromosome 22 that researchers already
believed was the location of a schizophrenia gene.
Working with researchers from the University of Pittsburgh, as well
as German and French collaborators, the team then studied DNA
from the blood of 150 patients with either schizophrenia or
manic-depressive illness and compared it to similar samples from
healthy individuals.
They found that more of the mentally ill patients had long C-A-G
segments than did the healthy controls, suggesting that the gene is
linked to the disorder.
The next step, Gutman said, is to study a larger number of patients
and confirm that their finding is real. The researchers also will attempt
to insert proteins produced from the mutated genes into cells grown
in
the laboratory to find out how the protein works and how it could
interfere with mental functioning.
More news reports on the same...
RESEARCHERS IDENTIFY CANDIDATE GENE LINKED TO SCHIZOPHRENIA
The genes that combine to produce the mental
distortions of schizophrenia have proved an elusive tangle for
researchers searching to unravel its cause and provide relief to the
60
million schizophrenics worldwide.
Repeatedly, genes have risen to the surface as potential causes for
the
disease only to have the link dissipate upon further analysis. However,
researchers have reliably noted that a region of chromosome 22 appears
to enhance the risk of developing the disorder.
Scientists from the University of California, Irvine (UCI), told attendees
at the 47th annual conference of the American Society of Human
Genetics Friday a newly discovered gene encoding a protein that slows
the firing of neurons may increase the risk of developing schizophrenia
as
well as bipolar disorder.
"We located the candidate gene in a region of chromosome 22 long
thought to be associated with these diseases, " said J. Jay Gargus,
a
UCI professor of physiology and biophysics. "The normal function of
this protein makes it reasonable that it could contribute to the disorders.
The gene, hSKCa3, that Gargus and his colleagues from the University
of Pittsburgh, the University of Frieburg, Germany, and the Centre
Hospital, in Rouffach, France, identified is a potassium channel. The
channel shuts off neuronal firing by turning off signals triggered
through
the N-methyl-D-aspartate (NMDA) receptor. Street drugs like PCP
cause a schizophrenia-like reaction by blocking the NMDA receptor.
"The NMDA receptor, however, has never been genetically linked to
mental illness, " Gargus said. "So, a protein that affects the activity
of
the NMDA receptor would be a reasonable candidate. "
Because some research has shown that schizophrenia and bipolar
disorder worsen with each generation, Gargus and his colleagues
decided to search for a cytosine-adenine-guanine (CAG) triplet repeat
pattern that has been implicated in other neurodegenerative diseases
like
Huntington's disease.
Gene Search Targeted More Than 100 Patients
The researchers studied 150 patients with schizophrenia from Europe
and the U.S. and a similar number of matched unaffected adults. Using
the criteria that 20 or more CAG repeats in the gene constituted an
excess number of repeats, the researchers found that 21 percent of
the
schizophrenic patients harbored 20 or more CAG repeats compared to
12 percent of the controls.
"These repeats appear to cause a graduated rather than a stochastic
change in the potassium channel, " Gargus said. "That would be in
character with the linkage found at chromosome 22 _ it is neither
necessary nor sufficient to cause disease, but it seems to increase
the
risk. "
Gargus believes that the polyglutamine encoded by the CAG repeats
may cause the proteins that make up the channel to stick together,
leaving the channel open longer than is normal. An open potassium
channel dampens neuronal activity by shutting down the NMDA
receptor.
"It is in theory acting like PCP, " Gargus said.
Gargus noted that his findings need to be repeated in a larger sample
and among families in order to establish the gene's role, if any, in
the
development of schizophrenia. In addition, he is working on testing
how
exactly the CAG repeats affect the activity of the potassium channel.
The University of California has patented hSKCa3 and the researchers
have been contacted by several companies hoping to develop drugs that
turn off the potassium channel.