Findings published in PLOS ONE scientific journal

MORGANTOWN, W.Va. – On June 26, 2000, former President Bill Clinton announced the completion of the world’s first survey of the entire human genome, the Human Genome Project. In his words, “Without a doubt, this is the most important, most wondrous map ever produced by humankind.”

Researchers at West Virginia University, in collaboration with an international consortium of geneticists and clinicians from Switzerland, France, Greece, and Germany, are working to understand the genetic basis of schizophrenia by sequencing those blueprints of the human genome for individuals diagnosed with the disorder, along with those of his or her healthy parents (trios). They have identified 18 different genes that possibly influence the incidence of schizophrenia, including Regulator of G protein Signaling type 12 (RGS12) that was originally cloned by WVU’s David Siderovski, Ph.D., and his colleagues in 1997.

By looking at genetic mutations that spontaneously arise in an individual suffering from schizophrenia, researchers are ultimately hoping to create new anti-psychotic medications that target the behavior of these specific genes.

“Schizophrenia is an extremely complex and multifaceted disorder, and the genetic underpinnings have remained largely unknown,” Dr. Siderovski, E.J. Van Liere professor and chair of the Department of Physiology and Pharmacology in the WVU School of Medicine, said.

Siderovski, along with his colleague Vincent Setola, Ph.D., assistant research professor in the Department of Physiology and Pharmacology, has spent the better part of his career delving into the role of RGS12 and other RGS proteins in diseases of the brain. Regulator of G-protein signaling type 12 is the protein encoded by the RGS12 gene. RGS12 has been identified as spontaneously mutated in one trio with schizophrenia in research conducted by the international consortium that included WVU, as well as through an additional independent study at Columbia University, providing verification of the importance of this gene mutation.

“For years, we have studied the RGS12 protein in isolation, in the petri dish, and in cells,” said Siderovski. “Having another completely independent cohort present the same results of an RGS12 mutation from their studies helps us to unequivocally move forward with finding a drug that targets this mutation.”

A highly inheritable, chronic, severe, and debilitating brain disorder, schizophrenia robs individuals of the ability to recognize what is real and what is not. People with the disorder may hear voices others don’t hear. They may believe that others are controlling their thoughts or plotting to harm them. They may not make sense when they talk and can sit for hours without moving or communicating.

“Many people in the general public believe that individuals with schizophrenia possess a multiple or ‘split’ personality, but this is an inaccurate representation,” Daniel Elswick, M.D., assistant professor in the Department of Behavioral Medicine and Psychiatry and co-director of the Thought Disorders Program at WVU Healthcare’s Chestnut Ridge Center, said. “Symptoms often begin in young adulthood and require management investment from the patient, their families, the community, and mental health and medical professionals.”

While the introduction of new medications is several years off, Siderovski is optimistic about advances in the research and the implications it can have on patients.

The Thought Disorders program at WVU works closely with patients, their families, and community agencies to provide qualitative management and encouragement of mental health recovery. The clinic also has established strategic partnerships with the scientific research community at the WVU Health Sciences Center to provide cutting-edge investigation and therapies for schizophrenia and its causes, outcomes, morbidities, and treatment.

Siderovski and Dr. Setola, along with their international consortium partners, recently had their research findings accepted for publication in the scientific journal PLOS ONE, an open access peer-reviewed scientific journal published by the Public Library of Science (PLOS). The article can be viewed online at www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0112745.

Siderovski’s long-standing research focus has been regulators of heterotrimeric G-protein signaling, having discovered the G-alpha GAP superfamily (RGS proteins) in 1996, based on genome sequence mining and yeast complementation. In 1999, Siderovski also discovered the GoLoco motif protein family of G-alpha-GDP dissociation inhibitors. Since these discoveries, his research into the function of novel regulators in G-protein signal transduction has led to more than 140 papers, reviews, and book chapters on the topic, as well as three different new investigator awards, including the John J. Abel award in 2004 from the American Society for Pharmacology and Experimental Therapeutics.

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