With the identification of the gene responsible for a newly recognized type of mental retardation, researchers at 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 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."
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| Depicted are MRI images of the brains of patients with bilateral frontoparietal polymicrogyria (BFPP), a recessive genetic disorder characterized by mental retardation, gait difficulty, language impairment, and seizures. Abnormalities are represented by yellow shaded areas. |
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.