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| |  Gene for Most Common Brain Defect Found PHILADELPHIA, Nov. 4, 1996 -- A team of researchers at The Children's Hospital of Philadelphia has identified the gene responsible for causing the most common brain anomaly in humans, holoprosencephaly (HPE). Literally, HPE means "one forebrain" because the two hemispheres of the brain do not form properly in utero. Embryonic developments that would have generated from the brain's midline are not triggered properly and as a result, facial and mental disorders occur in one in 16,000 live births. The finding appears in the November 1 issue of "Nature Genetics" and marks the first time that the human gene and the disease have been linked together. Maximilian Muenke, M.D., of the Division of Human Genetics and Molecular Biology at The Children's Hospital of Philadelphia, led team members Erich Roessler, M.D., Ph.D., and Karin Gaudenz, M.S., to this discovery. Holoprosencephaly's effects can vary substantially, from mild facial abnormalities to deformities that are incompatible with life outside of the womb. The severe form of HPE occurs in at least one in every 250 embryos and infants may be born without eyes or even with a single eye. However, because of HPE's effect on the brain's development, a majority of these infants die early in the womb. On the mild end of HPE's spectrum, children may have defects of the lip in combination with an underdeveloped nose and midface. In addition, some affected older children may be mentally retarded. The location of the gene potentially responsible for HPE was first pinpointed on chromosome 7 by Dr. Muenke's laboratory in 1993. Only a year later, the team was able to confirm that this same gene was indeed involved in families where several relatives had HPE. "After 10 years of studying children with HPE, I am so pleased that the families who helped us will potentially benefit from our finding," said Dr. Muenke. "It is because of these family members that the faulty gene was discovered." Dr. Muenke and his team will now begin to study milder forms of holoprosencephaly. "The long-term goal of my lab's research is to better understand the genetic causes of mental retardation and developmental disabilities and eventually devise therapies which will benefit affected children and their families," said Dr. Muenke. "The more we know, the more we can help these families," he said. This gene responsible for HPE is actually already named. It is called the Sonic Hedgehog (SHH), named for the popular video game by the Harvard scientists who first identified the gene in 1992. Since then, SHH has been one of the most studied genes in biology. Although the gene has been well characterized in other organisms, this is the first time that the link between SHH and HPE has been identified. "This is one of the most crucial genes controlling early embryonic development," said Dr. Roessler. "The discovery that this gene contributes to HPE will allow us to search for additional genes involved in children with defects of the face and brain," he said. Dr. Muenke's research of holoprosencephaly was sponsored in part by the National Institutes of Health and the March of Dimes Birth Defects Foundation. Contributing to The Children's Hospital of Philadelphia's team effort was Dr. Lap-Chee Tsui at the Hospital for Sick Children in Toronto. The Children's Hospital of Philadelphia, the nation's first children's hospital, is a leader in patient care, education and research. This 304-bed multispecialty hospital provides comprehensive pediatric services to children from birth through age 19.
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