2000 Release: Fourth Holoprosencephaly Gene

National Human Genome Research Institute

National Institutes of Health
U.S. Department of Health and Human Services

Genetic Mutation Causes Common Defect In Early Development of Human Forebrain

"TGIF" Gene Important In Determining Brain's Split Into Left and Right Hemispheres

June 2000

BETHESDA, Md. - An international team led by scientists at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) has located one of the genes that can cause holoprosencephaly, the most common structural defect of the developing forebrain in humans. It results in varying degrees of mental retardation. The finding suggests that the gene, dubbed TGIF, plays an important role in the brain's separating into left and right hemispheres during fetal development.

TGIF, or TG-interacting factor, was mapped to a region on human chromosome 18, the researchers report in the June issue of the journal Nature Genetics. Collaborating with the NHGRI scientists were colleagues at the Children's Hospital of Philadelphia; Memorial Sloan-Kettering Cancer Center in New York; Baylor College of Medicine in Houston, Texas; Australia's Royal Alexandra Hospital for Children; Germany's Altonauer Kinderkrankenhaus; and University of Sao Paulo in Brazil.

"This finding helps us understand holoprosencephaly and what can go wrong very early during embryonic development," said Dr. Maximilian Muenke, NHGRI scientist and chief of the institute's medical genetics branch.

"But by understanding holoprosencephaly, we also gain a better understanding of normal brain development," added Dr. Muenke, one of the paper's authors.

Holoprosencephaly, or HPE, occurs in one of every 16,000 live births. However, the disorder affects as many as one in every 250 fetuses, most of which die in the womb. Children born with mild HPE appear to be clinically normal, yet they still carry the mutation. In children with more severe HPE, there may be incomplete separation of not only the brain's hemispheres, but also the face's left and right eye fields, in addition to other facial defects, such as misshapen heads or cleft palates.

On a molecular level, TGIF plays an important role in two separate pathways, or series of biochemical steps. One pathway involves interference with the chemical retinoic acid. "This is intriguing since, in animal models, exposure to retinoic acid has been shown to cause HPE," said Muenke. The other pathway involves a class of signaling molecules important in the development of the forebrain and other head structures.

The TGIF gene is the fourth found in humans to be involved in HPE. Others include the so-called "Sonic Hedgehog" gene on chromosome 7, ZIC2 on chromosome 13, and SIX3 on chromosome 2. However, there may be at least eight more genes on different chromosomes, which Muenke's lab is currently trying to identify.

"It took us and our collaborators four years to identify the first four genes," Muenke noted. "Now, with the success of the Human Genome Project, I think it will take much less time to identify further genes that are involved in HPE."

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Last Reviewed: September 24 2010