From The Quarterly, Summer 2012

Isolated populations with relatively homogeneous gene pools make excellent natural laboratories for genetic research. One such study examines the genetics of schizophrenia. This research focuses on the descendents of a community founded in the 1700s by Spanish conquistadors who intermingled with indigenous families in a remote, mountainous area of Costa Rica that remained largely untouched by the outside world for 200 years.



Researchers have identified many genes they believe to be potential candidates, in mutated form, as contributors to schizophrenia—not any one gene acting alone, but rather interacting with other genes and with environmental triggers. Neuregulin-1 is one such gene established by researchers as having a high likelihood of being associated with schizophrenia. In its normal form, neuregulin-1 plays important roles in nerve-cell communication and other key brain functions.



Consuelo Walss-Bass, Ph.D. and colleagues have sequenced the neuregulin-1 gene in members of the Costa Rican community who have schizophrenia. Using powerful sequencing technology, the researchers identified a particular mutation occurring in 14 out of 17 families studied. Consulting the excellent genealogical records kept in Costa Rica, they have been able to pinpoint a common founding ancestor of the 14 families.



The researchers have further been able to show that people with the identified neuregulin-1 mutation have elevated levels of inflammatory markers, immune-cell products called cytokines. Cytokines are produced during stress or infections, which are environmental threats that are believed may trigger schizophrenia symptoms in genetically susceptible people. Cytokines are a very active focus of current research since it has been determined that these molecules can cross the blood-brain barrier, which was not previously thought possible.



The researchers hypothesized an aberration in the function of the protein encoded by the mutated neuregulin-1 gene, which has been corroborated by research elsewhere. Specifically, the mutation causes the protein to not be cut, and therefore it does not work properly. Importantly, the Walss-Bass team has recently shown that in brains from individuals with schizophrenia the neuregulin-1 protein is not properly cut. The next step is to ascertain if the neuregulin-1 mutation is functional; is it actually causing disease? To do so, researchers will use genetically engineered animal models to see if the mutation that was identified translates, in the animals, into behavioral problems that are analogous

to problems seen in people with schizophrenia.

Consuelo Walss-Bass, Ph.D.

2004 and 2007 NARSAD Young Investigator Grantee

Associate Professor

Department of Psychiatry

University of Texas Health Science Center at San Antonio