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Collaborations Yield New Discoveries In Psychiatric Genetics

Date:
October 7, 2005
Source:
Rutgers, the State University of New Jersey
Summary:
Two New Jersey research teams are reporting discoveries about the biological nature of psychiatric disorders that may bring them closer to the ultimate goal of finding cures for complex diseases, such as autism and schizophrenia. Scientists at Rutgers University in collaboration with colleagues at the University of Medicine and Dentistry of New Jersey (UMDNJ) have unveiled new information regarding the genetic, cellular and neurological bases of susceptibility to these diseases.

NEW BRUNSWICK/PISCATAWAY, N.J. -- Two New Jersey research teams arereporting discoveries about the biological nature of psychiatricdisorders that may bring them closer to the ultimate goal of findingcures for complex diseases, such as autism and schizophrenia.

Scientists at Rutgers, The State University of New Jersey, incollaboration with colleagues at the University of Medicine andDentistry of New Jersey (UMDNJ) have unveiled new information regardingthe genetic, cellular and neurological bases of susceptibility to thesediseases.

Using data drawn from the Rutgers Cell and DNA Repository on518 families, each with multiple autistic children, James Millonig andLinda Brzustowicz, assisted by Emanuel DiCicco-Bloom, led a team thatfurther substantiates the link between autism and Engrailed 2 (EN2), agene important in central nervous system development. Their research ispresented in the November issue of the American Journal of HumanGenetics (AJHG).

Millonig and Brzustowicz had previously demonstrated anassociation with the gene in a sample of 167 families with autism. Thenew study adds another 351 families and now provides convincingstatistical support for the existence of a mutated form of EN2 thatincreases the risk for autism. The statistics also showed EN2 maycontribute to up to 40 percent of autism cases in the generalpopulation.

EN2 is involved with the development of the cerebellum, thepart of the brain that governs movement and, to some extent, languageand speech. A change in EN2 could potentially produce symptoms ofautism. Further work on characterizing EN2 and on the identification ofadditional autism susceptibility genes will be funded by a $2.3 milliongrant to Millonig and DiCicco-Bloom and a linked $2.5 million grant toBrzustowicz from the National Institute of Mental Health (NIMH) toidentify additional autism susceptibility genes.

Millonig is an assistant professor of neuroscience and cellbiology at UMDNJ-Robert Wood Johnson Medical School (RWJMS) and anadjunct assistant professor in Rutgers' department of genetics. He isalso a resident faculty member of the Center for Advanced Biotechnologyand Medicine, a research enterprise jointly operated by bothinstitutions. Brustowicz is a professor of genetics at Rutgers, a boardcertified psychiatrist and an associate professor of psychiatry at theUMDNJ-New Jersey Medical School; DiCicco-Bloom is a professor ofneuroscience and cell biology at UMDNJ-RWJMS.

A second team led by Brustowicz and Bonnie Firestein, anassistant professor in Rutgers' department of cell biology andneuroscience, implicated a gene called CAPON in schizophrenia. A reportof their research is available in the online journal PLoS (PublicLibrary of Science) Medicine.

CAPON had been previously identified as a gene involved in theprocesses of communication between neurons in the brain. The Rutgersteam identified a new variant of the CAPON gene that produces a shorterprotein product. Using a sample of post-mortem brains, the researchersfound elevated levels of this variant in the brains from individualswith schizophrenia and bipolar disorder. Brzustowicz and Firestein alsooffered their conclusions about how CAPON operates in its signalingcontext, functional evidence supporting the connection between the geneand these psychiatric diseases.

Researchers agree that there are environmental contributors tosusceptibility to psychiatric disorders, but based on inheritancepatterns of these diseases seen in families, the genetic componentappears to be quite strong. The inheritance picture, however, is farfrom clear. It is not like the simple, one-gene models for eye color orblood type or found in such diseases as muscular dystrophy or cysticfibrosis.

"The diseases we study are polygenic, meaning that many genesare likely to contribute, but how many genes there are and how theyinteract are unknowns," Millonig said. "Identifying a gene in a complexdisease may give more insight into the pathways involved -- it helpsyou begin to unravel what is at its basis."

Earlier genetic studies of a Canadian study population of largefamilies with a high incidence of schizophrenia pointed the way toCAPON. The gene was known to code for a protein that functioned in aneuronal pathway thought to be linked to schizophrenia. Beyondestablishing a mere statistical connection between a gene and apsychiatric disorder -- CAPON and schizophrenia -- Firestein andBrzustowicz provided functional evidence as to the nature of theconnection. "We began with a purely genetic approach and identified aregion of chromosome 1 that seemed very likely to contain asusceptibility gene, but then moved on to studies of gene expression inhuman brains to search for convincing evidence of a functional role forCAPON in schizophrenia," Brzustowicz said.

The researchers discovered two forms of the gene are normallyexpressed in human brain, a long form and a short form. Based on whatis known about the gene interactions, it is predicted that when theshort form is present in excess, it will disrupt the signaling pathway,resulting in decreased function, reduced signaling and lesscommunication, all of which are suspected to occur in schizophrenia,Firestein said. The published information includes a detaileddescription of how this is thought to occur.

The research team then analyzed the post-mortem brains -- 35from individuals with schizophrenia, 35 from bipolar individuals and 35from those with normal brains -- and found significantly increasedlevels of the short form in the specimens from individuals withpsychiatric disorders.

While many genes have been implicated in schizophrenia based onfamily studies, there has been little functional evidence foralteration in the proteins that are actually involved, but with CAPONthere does, indeed, appear to be functional evidence.

"If CAPON really does disrupt this cellular pathway so theneurons cannot signal when and where they are supposed to, there is apoint of entry for therapeutics," Firestein said. "While we can't makethe therapeutics right now, we may have established some targets."


Story Source:

The above story is based on materials provided by Rutgers, the State University of New Jersey. Note: Materials may be edited for content and length.


Cite This Page:

Rutgers, the State University of New Jersey. "Collaborations Yield New Discoveries In Psychiatric Genetics." ScienceDaily. ScienceDaily, 7 October 2005. <www.sciencedaily.com/releases/2005/10/051007091856.htm>.
Rutgers, the State University of New Jersey. (2005, October 7). Collaborations Yield New Discoveries In Psychiatric Genetics. ScienceDaily. Retrieved August 27, 2014 from www.sciencedaily.com/releases/2005/10/051007091856.htm
Rutgers, the State University of New Jersey. "Collaborations Yield New Discoveries In Psychiatric Genetics." ScienceDaily. www.sciencedaily.com/releases/2005/10/051007091856.htm (accessed August 27, 2014).

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