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April 08, 2004


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HARVARD GAZETTE ARCHIVES

Newly identified gene linked to brain development

Discovery sheds light on frontal lobe evolution

With the identification of the gene responsible for a newly recognized type of mental retardation, researchers at Harvard-affiliated Beth Israel Deaconess Medical Center (BIDMC) have also discovered what appears to be the key target in the evolution of the frontal lobes of the brain's cerebral cortex. The findings, reported in the March 26 issue of the journal Science, offer a key insight into the complex puzzle of human brain development - and the evolution of human behavior.

"The cerebral cortex is the part of the brain that distinguishes humans from other species," explains the study's senior author, Christopher A. Walsh, a Howard Hughes Medical Institute investigator in the Neurogenetics Division at BIDMC and Bullard Professor of Neurology at Harvard Medical School. "And the frontal lobes are the part of the cortex that govern social function, cognition, language, and problem solving. Patients with damage to the frontal lobes exhibit changes in behavior, and frontal lobotomies were once performed to alter aggressive behavior."

Bilateral frontoparietal polymicrogyria (BFPP), a recessive genetic disorder characterized by mental retardation, gait difficulty, language impairment, and seizures, results in severely abnormal architecture of the brain's frontal lobes, as well as milder involvement of parietal and posterior parts of the cerebral cortex.

In this new study, lead author Xianhua Piao and colleagues used magnetic resonance imaging (MRI) to identify BFPP patients, and then used linkage analysis, homozygosity mapping, and candidate gene analysis to identify the BFPP gene as GPR56, located on an area of chromosome 16.

"We showed that mutations in GPR56, which encodes an orphan G protein-coupled receptor [GPCR], were responsible for BFPP," explains Piao. GPR56 is expressed in the neural stem cells produced in the cerebral cortex, and plays an especially important role in the frontal portions of the cortex.

Walsh's laboratory uses gene mapping to identify genes that disrupt the normal development of the brain's cerebral cortex, thereby helping to define the clinical syndromes of certain human developmental disorders and develop diagnostic tests for at-risk individuals. These new findings, he says, suggest that GPR56 may have been a key target in the evolution of the cerebral cortex.

"The frontal lobes of the human brain are the most highly developed part relative to other animals and it has long been thought that the evolution of the frontal lobes parallels the development of human communication and civilization," Walsh adds. "The GPR56 gene is only found in higher animals that possess a frontal lobe. It has undergone significant changes, even among these species, suggesting it may be a target of evolution.

"Being able to access the complete sequence of the human genome has allowed us to identify increasing numbers of genes that are required for cortical development," he adds. "Although these genes cause mental retardation, by studying the biological function of their gene products we also gain insight into the normal development and function of the human brain."

In addition to Walsh and Piao, study co-authors include BIDMC researchers R. Sean Hill, Adria Bodell, and Bernard S. Chang; and A. James Barkovich of the University of California, San Francisco, as well as many clinicians from around the world who provided DNA samples. The study was funded by the Howard Hughes Medical Institute and by grants from the National Institutes of Health, the March of Dimes, and the McKnight Foundation. Beth Israel Deaconess Medical Center is a major patient care, teaching, and research affiliate of Harvard Medical School, ranking third in National Institutes of Health funding among independent hospitals nationwide.







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