In a study supported by the National Institutes of Health, scientists at the University of Iowa have just identified one such gene as the cause of Rieger syndrome, a rare disorder that leaves its mark on many parts of the body. Affected individuals have facial bone abnormalities, small or missing teeth, and serious eye disorders that lead to glaucoma in 50 per cent of the cases. There can also be involvement of the pituitary gland and other organs. This is the first finding of a gene that results in glaucoma in a high proportion of affected patients. The findings are reported in the December issue of Nature Genetics.
Although Rieger syndrome is a rare disorder in which glaucoma strikes in childhood, finding the responsible gene gives scientists a tool to study the causes of the more common forms of adult glaucoma. It is also the first gene of its kind to be associated with the failure of tooth development.
The search for the Rieger gene, supported primarily by NIH's National Institute of Dental Research, led Drs. Elena Semina, Jeffrey Murray, and colleagues on a 5-year chase, sorting through the genes of 10 families. The long hunt culminated with the discovery that Rieger syndrome is caused by mutations in a new type of human "homeobox" gene. Members of this fascinating gene family are known to determine body shape in most forms of animal life and have been traced back to prehistoric worms that crawled on the earth over 600 million years ago.
The Rieger gene, named RGS, has a unique structure that ties it to a special group of homeobox genes first identified in the fruit fly, but not previously found in humans. Related genes in the fly are involved in the development of the insect's head region.
The investigators have since discovered a closely related gene in mice that appears to be similar to the Rieger gene in both structure and function. The mouse studies further support the role of the RGS gene in the specific abnormalities that are seen in Rieger patients. In the developing mouse embryo, the gene is switched on in the eyes, jaws, umbilical cord, and pituitary, areas particularly hard hit in Rieger syndrome.
The investigators point out that RGS mutations were not detected in all Rieger patients. In such cases, they say, the disorder may be due to mutations in part of the gene not yet scanned, or result from mutations in a closely related gene.
The study was carried out by an international group of investigators, including Drs. Elena V. Semina, Rebecca Reiter, Nancy Leysens, W. Lee M. Alward, and Jeffrey C. Murray, University of Iowa; Dr. Kent W. Small, UCLA Medical Center; Dr. Nicole A. Datson, Sylvius Laboratoria, The Netherlands; Dr. Jacqueline Siegel-Bartelt, The Hospital for Sick Children, Ontario, Canada; Dr. Diane Bierke-Nelson, The Duluth Clinic, Minnesota; Dr. Pierre Bitoun, Hospital Jean Verdier, Bondy cedex, France; Dr. Bernhard U. Zabel, Klinikum Johannes Gutenberg-Universitat Mainz, Germany; and Dr. John C. Carey, University of Utah Health Sciences Center.