Rare gene glitch may hold clues for schizophrenia

Feb 24, 2011 By Jules Asher
In this family pedigree, the VIPR2 mutation was inherited by at least one of two male offspring who developed schizophrenia (dark squares) from an unaffected mother (circle at top). Credit: Jonathan Sebat, Ph.D., UC San Diego

Scientists are eyeing a rare genetic glitch for clues to improved treatments for some people with schizophrenia -- even though they found the mutation in only one third of 1 percent of patients.

In the study, funded in part by the National Institutes of Health, patients were 14 times more likely than controls to harbor multiple copies of a gene on . The were in the gene for VIPR2, the receptor for vasoactive intestinal peptide (VIP) — a chemical messenger known to play a role in brain development. An examination of patients' blood confirmed that they had overactive VIP activity.

Discovery of the same genetic abnormality in even a small group of patients buoys hopes for progress in a field humbled by daunting complexity in recent years. The researchers’ previous studies had suggested that the brain disorder that affects about 1 percent of adults might, in many cases, be rooted in different genetic causes in each affected individual, complicating prospects for cures.

"Genetic testing for duplications of the VIP receptor could enable early detection of a subtype of patients with schizophrenia, and the receptor could also potentially become a target for development of new treatments," explained Jonathan Sebat, Ph.D., of the University of California, San Diego, who led the research team. "The growing number of such rare duplications and deletions found in schizophrenia suggests that what we have been calling a single disorder may turn out, in part, to be a constellation of multiple rare diseases."

Sebat, a grantee of the NIH's National Institute of Mental Health — and colleagues at 14 research centers world-wide — report on their findings Feb. 23, 2011, in the journal Nature.

"Although such copy number variations may explain only a small fraction of cases, these rare mutations can yield important clues to the underlying causes of more common forms," noted NIMH Director Thomas R. Insel, M.D. "This new finding with VIPR2 suggests a series of important follow up studies, even in people without the mutation."

Schizophrenia is known to have a strong genetic component — having a parent or sibling with the disorder increases one's risk tenfold. Yet, genetic studies have so far explained relatively few cases of the illness. As hopes wane that common genetic variations might account for many cases, evidence is mounting that patients harbor disproportionately large numbers of individually rare copy number variations (CNVs) – some shared in families, but many apparently unique to one individual.

The VIPR2 CNV is among the first to implicate a specific gene and neurobiological pathway in schizophrenia. CNVs previously identified, spanning dozens of , were too large to yield such clues. In the new genome-wide scan, Sebat and colleagues found the mutation in 29 of 8290 patients (.35 percent) compared to only 2 of 7431 healthy controls. A few other schizophrenia-linked CNVs seen in previous studies were also detected.

VIP and its receptor are known to play a role in regulating the growth of neurons and in learning and memory. They are also expressed in the immune and cardiovascular systems and in the gut — hence its name.

When VIP binds to the VIPR2 receptor on a neuron, it triggers a key relay chemical within the cell, called cyclic AMP. The researchers found that both VIP and cyclic AMP were overactive in blood cells of patients with the VIPR2 mutations.

"It's likely that cyclic AMP signaling is disturbed in a larger fraction of patients, so it's possible that a treatment that targets VIPR2 might have benefits even for people who don’t have mutations in the VIPR2 gene," said Sebat. "It looks like the volume is turned-up in the whole VIP signaling pathway."

Since the mutations lead to an overexpression of VIPR2, agents that block the receptor, which already exist, might hold potential for treatment development, he added.

In addition to genetic screening of patients for such personalized medicine, Sebat sees opportunities in the new findings for neuroimaging studies. "We must determine how over-expression of VIPR2 impacts the growth, differentiation and function of neurons" and how that influence behavior. Knowing where the VIPR2 gene is expressed in the human brain can point us to specific regions where VIP activity levels may differ between people who carry this mutation and those who don’t.”

Despite the challenges posed by the complexities of CNVs, Sebat is upbeat about prospects for ultimately making sense of the emerging evidence about schizophrenia genetics.

"We hypothesize that the many different genetic causes of schizophrenia may have something in common," he said. “There may be larger groups of patients who may not share the same mutation but, may share the same underlying neurobiological defect.”

Explore further: First genetic link discovered to difficult-to-diagnose breast cancer sub-type

More information: Duplications of the Neuropeptide Receptor VIPR2 Confer Significant Risk for Schizophrenia. Vacic V, et al. Nature. 2011 Feb 23.

Provided by National Institutes of Health

5 /5 (1 vote)
add to favorites email to friend print save as pdf

Related Stories

Schizophrenia gene mutation found; target for new drugs

Feb 02, 2011

In a major advance for schizophrenia research, an international team of scientists, led by Jonathan Sebat, PhD, assistant professor of psychiatry and cellular and molecular medicine at the University of California, San Diego ...

Tiny, spontaneous gene mutations may boost autism risk

Mar 15, 2007

Tiny gene mutations, each individually rare, pose more risk for autism than had been previously thought, suggests a study funded in part by the National Institute of Mental Health, a component of the National Institutes of ...

Rare mutation dramatically increasing schizophrenia risk

Oct 25, 2009

An international team of researchers led by geneticist Jonathan Sebat, Ph.D., of Cold Spring Harbor Laboratory (CSHL), has identified a mutation on human chromosome 16 that substantially increases risk for schizophrenia.

Recommended for you

Refining the language for chromosomes

Apr 17, 2014

When talking about genetic abnormalities at the DNA level that occur when chromosomes swap, delete or add parts, there is an evolving communication gap both in the science and medical worlds, leading to inconsistencies in ...

Down's chromosome cause genome-wide disruption

Apr 16, 2014

The extra copy of Chromosome 21 that causes Down's syndrome throws a spanner into the workings of all the other chromosomes as well, said a study published Wednesday that surprised its authors.

User comments : 0

More news stories

Filipino tests negative for Middle East virus

A Filipino nurse who tested positive for the Middle East virus has been found free of infection in a subsequent examination after he returned home, Philippine health officials said Saturday.

Study says we're over the hill at 24

(Medical Xpress)—It's a hard pill to swallow, but if you're over 24 years of age you've already reached your peak in terms of your cognitive motor performance, according to a new Simon Fraser University study.

NASA's space station Robonaut finally getting legs

Robonaut, the first out-of-this-world humanoid, is finally getting its space legs. For three years, Robonaut has had to manage from the waist up. This new pair of legs means the experimental robot—now stuck ...

Ex-Apple chief plans mobile phone for India

Former Apple chief executive John Sculley, whose marketing skills helped bring the personal computer to desktops worldwide, says he plans to launch a mobile phone in India to exploit its still largely untapped ...

Egypt archaeologists find ancient writer's tomb

Egypt's minister of antiquities says a team of Spanish archaeologists has discovered two tombs in the southern part of the country, one of them belonging to a writer and containing a trove of artifacts including reed pens ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.