A rare genetic mutation that is linked to schizophrenia has just been identified and published in the journal Molecular Psychiatry. A group of experts from Johns Hopkins University studied the members of a family with a high rate of mental illness; they strongly believe that a mutation in the gene Neuronal PAS domain protein 3 (NPAS3) is in some way responsible for the development of mental illnesses such as schizophrenia.

NPAS3 is responsible for regulating and making sure that healthy neurons are consistently developed, particularly in the hippocampus – a region of the brain affected in schizophrenia. An abnormal mutation of this gene was found among certain members of a single family – the mutation caused the NPAS3 to function improperly, which was detrimental to for brain development. The gene assigns instructions for the production of a protein containing 933 amino acids.

The lead author of the study Frederick C. Nucifora Jr., Ph.D., D.O., M.H.S., said:

“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. We could definitely use better medicines.”

Schizophrenia is a somewhat common condition, affecting seven in every 1,000 American adults; it is characterized by severe hallucinations, delusions and overall impaired cognition. It is thought to be caused by a mixture of environmental and genetic factors.

The authors believe that studying the biological role of NPAS3 will provide insight into how other genes may also be the cause of mental illnesses like schizophrenia.

The researchers collected blood samples from 34 people with schizophrenia or schizoaffective disorder and analyzed them to study their DNA. Each of the participants belonged to families with a history of mental illness. The scientists were focusing on seeking out people with a NPAS3 mutation, they ended up finding one and carried out a series of blood tests on members of that family, including two parents and four adult children.

Results showed that the mother who has schizophrenia, as well as her two children with the same disorder and another suffering from depression, all shared the same mutant genetic variation of NPAS3. The mutated version of the gene had one single difference in that an isoleucine took the place of a valine. The authors are not yet sure how this change affects the function of the gene, though.

In order to determine whether this specific mutation has any effect on the way NPAS3 should normally function, Nucifora and his team carried out a separate experiment. The researchers grew neurons with mutated and normal versions of the gene in a dish and analyzed any significant differences. They found that the normal version of the gene had very long extensions which enables it to make good neuronal connections with other cells – the mutated version had much shorter extensions in comparison.

Nucifora said:

“We showed that the mutation does change the function of NPAS3, with potentially harmful effects in neurons. 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.”

The team is now planning on conducting further research in mice with the NPAS3 mutation.

Nucifora added:

“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.”

A previous study carried out by researchers from the Universite de Montreal found evidence to suggest that a mutation in the SHANK3 gene is also associated with an increased risk of schizophrenia.

Written by Joseph Nordqvist