Newly identified gene linked to brain development
Date: 3/26/2004
Contact: Bonnie Prescott
Phone: 617-667-7306
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BOSTON - 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, 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, MD, PhD, 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 MD, PhD, 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. The medical center is clinically affiliated with the Joslin
Diabetes Center and is a founding member of the Dana-Farber/Harvard
Cancer Care Center. BIDMC is the official hospital of the Boston Red
Sox. For more information, visit www.bidmc.harvard.edu.
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