Evidence mounts for role of mutated genes in development of schizophrenia

January 22, 2013, Johns Hopkins University School of Medicine

Johns Hopkins researchers have identified a rare gene mutation in a single family with a high rate of schizophrenia, adding to evidence that abnormal genes play a role in the development of the disease.

The researchers, in a report published in the journal , say that family members with the mutation in the gene Neuronal PAS domain protein 3 (NPAS3) appear at high risk of developing or another debilitating .

Normally functioning NPAS3 regulates the development of healthy neurons, especially in a region of the brain known as the , which appears to be affected in schizophrenia. The Johns Hopkins researchers say they have evidence that the mutation found in the family may lead to abnormal activity of NPAS3, which has implications for and function.

"Understanding the molecular and biological pathways of schizophrenia is a powerful way to advance the development of treatments that have fewer side effects and work better than the treatments now available," says study leader Frederick C. Nucifora Jr., Ph.D., D.O., M.H.S., an assistant professor of psychiatry and at the Johns Hopkins University School of Medicine. "We could definitely use better medicines."

Along with , it is widely believed that many genes play some role in causing schizophrenia, a disease characterized by a variable combination of hallucinations, delusions, impaired cognition and a loss of drive and initiative. The disorder strikes an estimated seven in every 1,000 adults in the United States. While the Johns Hopkins experiments to date show that the NPAS3 mutation is rare, Nucifora says learning as much as possible about the biological role of NPAS3 will likely lead to a better understanding of how other genes contribute to the development of schizophrenia, even in the absence of the NPAS3 mutation.

For the study, Nucifora and his team used blood samples to search the DNA of 34 people with schizophrenia or a related condition, schizoaffective disorder. All 34 were members of families in which more than one person had the disease. The investigators were specifically looking for NPAS3 —previous research suggested it could be involved in schizophrenia—and found it in one of the families.

By analyzing from that single family—two parents and four adult children—they found that the mother, who has schizophrenia, her two children with schizophrenia, and her child with major depression all had the mutant version of NPAS3. The NPAS3 gene provides instructions for the production of a protein that contains 933 amino acids. The altered gene led to a single flaw: a valine was switched to an isoleucine. Nucifora says it is not yet known how this single mutation affects the function or structure of NPAS3. A possible hint comes from the finding of other investigators that a change from valine to isoleucine in a protein known as APP is linked to Alzheimer's disease.

Nucifora cautions that, by itself, finding a mutation in a single family with mental illness doesn't establish the altered gene as the cause of the illness. Nucifora and his colleagues therefore set out to determine whether the mutation plays any role in the function of NPAS3, which serves as a master switch in cells, controlling the fate of many other genes involved in brain development and metabolism.

To do that, Nucifora and his colleagues grew neurons with either normal or mutated copies of NPAS3 in a dish, and found that the healthy neurons grew nice long extensions, a process that typically allows them to make good connections with other cells and is therefore critical for brain function. In neurons with the mutated gene, the extensions were abnormally short.

Other genes believed to be involved in mental illness also have been found to disrupt the growth of longer neuronal extensions.

"We showed that the mutation does change the function of NPAS3, with potentially harmful effects in neurons," he says. "The next step is to figure out exactly how the genetic disruption alters neuronal function, and how these abnormal neurons influence the broader function of the brain."

Nucifora and his team are now working to create a mouse with the NPAS3 mutation. "If this mutation in NPAS3 is indeed important for human disease, then we should detect abnormalities in the neurons of mice with mutant NPAS3, and the mice should have impairments in learning, memory and social behavior," he says.

Explore further: Researchers link two biological risk factors for schizophrenia

Related Stories

Researchers link two biological risk factors for schizophrenia

July 17, 2012
(Medical Xpress) -- Johns Hopkins researchers say they have discovered a cause-and-effect relationship between two well-established biological risk factors for schizophrenia previously believed to be independent of one another.

Genetic risk, stressful early infancy join to increase risk for schizophrenia

March 26, 2012
Working with genetically engineered mice and the genomes of thousands of people with schizophrenia, researchers at Johns Hopkins say they now better understand how both nature and nurture can affect one’s risks for schizophrenia ...

Schizophrenia: Small genetic changes pose risk for disease

December 16, 2011
(Medical Xpress) -- Carrying single DNA letter changes from two different genes together may increase the risk of developing schizophrenia, Johns Hopkins researchers reported in the November 16 issue of Neuron.

Rare genetic disorder points to molecules that may play role in schizophrenia

October 9, 2012
Scientists studying a rare genetic disorder have identified a molecular pathway that may play a role in schizophrenia, according to new research in the October 10 issue of The Journal of Neuroscience. The findings may one ...

Recommended for you

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

Study advances gene therapy for glaucoma

January 16, 2018
While testing genes to treat glaucoma by reducing pressure inside the eye, University of Wisconsin-Madison scientists stumbled onto a problem: They had trouble getting efficient gene delivery to the cells that act like drains ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

How incurable mitochondrial diseases strike previously unaffected families

January 15, 2018
Researchers have shown for the first time how children can inherit a severe - potentially fatal - mitochondrial disease from a healthy mother. The study, led by researchers from the MRC Mitochondrial Biology Unit at the University ...

Genes that aid spinal cord healing in lamprey also present in humans

January 15, 2018
Many of the genes involved in natural repair of the injured spinal cord of the lamprey are also active in the repair of the peripheral nervous system in mammals, according to a study by a collaborative group of scientists ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.