October 31, 1996
SickKids scientists find the gene for Cyclops
TORONTO - When the Greek poet Homer wrote The Odyssey, was he describing the one-eyed Cyclops from personal observation? His description may have been accurate, given a recent discovery by scientists at The Hospital for Sick Children (SickKids) and The Children's Hospital of Philadelphia.
A team of researchers has identified a gene which causes holoprosencephaly, a disease which can lead to major structural defects of the head. In its most severe form - known as cyclopia - patients have a single eye in the middle of their face and no nose. The symptoms of the less severe form of the disease include defects of the upper lip and/or nose. The research, headed by Drs. Lap-Chee Tsui, Stephen Scherer and Elena Belloni of SickKids and Dr. Maximilian Muenke of The Children's Hospital of Philadelphia, is reported in two papers in the November 1 issue of the scientific journal Nature Genetics.
"Not only did Homer refer to cyclopia, but it's mentioned in the writings of the early Romans," explains Dr. Scherer, a molecular biologist at SickKids. "If based on fact, these accounts represent the earliest documentation of survivors of the severe form of holoprosencephaly."
Accounts of the disease did not appear in the scientific literature until the late eighteenth century.
The holoprosencephaly gene, called Sonic Hedgehog (SHH), is located on human chromosome 7. It was identified in the fruitfly in 1992 and the human gene was later found by Harvard scientists who named it after the popular video game. Since its discovery, SHH has been one of the most studied genes in all of biology. Although the gene has been well characterized in other organisms, this is the first time a link between the human gene and disease has been discovered.
Holoprosencephaly in humans occurs in one in 16,000 live births and one in 250 induced abortions. Most children with the severe forms of the disease do not survive past one year of age. Approximately four cases of holoprosencephaly are seen at SickKids per year. The same disease is known to occur in virtually every species in the animal kingdom.
"This gene has remarkable properties that allow it to control the early embryonic development of several body parts, including the limbs and the head," explains Dr. Tsui, also a Professor of Molecular and Medical Genetics, U of T. "Animal studies show that if you insert SHH protein in the right place in a developing limb it will result in two mirror image limbs instead of one."
According to Dr. Tsui, the discovery highlights the combined expertise in basic and clinical research at The Hospital for Sick Children and the quality of the hospital's human genome research facilities. "Our team has the best gene map of human chromosome 7 in the world," says Tsui, who led the team which discovered the cystic fibrosis gene on chromosome 7 in 1989. Their chromosome 7 mapping project is part of the international effort to map and sequence the entire human genome.
Tsui, Scherer and Belloni discovered that the Sonic Hedgehog gene was in close proximity to a chromosomal abnormality detected in a holoprosencephaly patient seen at SickKids by clinical geneticist Dr. Jacqueline Siegel-Bartelt. It was this observation that initiated the work which eventually linked SHH with holoprosencephaly. The next step in the research will be to discover how mutations of SHH cause the different clinical presentations of the disease.
Key collaborators in this work were Drs. Ben Koop and Duane Martindale of the University of Victoria, BC, and Helen Donis-Keller, Washington University in St. Louis. The research at The Hospital for Sick Children was supported by grants from the Canadian Genetic Diseases Network, the Canadian Genome Analysis and Technology Program, and the Howard Hughes International Research Scholar Program.
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