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Cracking the glaucoma genetic code: Families are key to progress
Researchers are working toward identifying and flushing out the locus and mutations of GLC1, the gene for open-angle glaucoma.
WAILEA, Hawaii — Deconstructing the genetic map of glaucoma may help physicians in the future to detect glaucoma early and respond with preventive treatment, said a glaucoma specialist speaking here.
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“In the next 10 years, we are going to see that about half of open-angle glaucoma has a genetic component. We will determine the genes associated with this condition and compare and contrast them in how they respond to medication,” John R. Samples, MD, said at Hawaii 2003: the Royal Hawaiian Eye Meeting.
During his presentation updating the genetics of open-angle glaucoma, Dr. Samples said great strides have been made in the evolving field of genetic eye research.
“At present, there are six known loci for open-angle glaucoma,” he said.
A locus is the site on a chromosome where the gene for a particular trait is located. Genetic researchers have discovered six known loci for open-angle glaucoma. At these sites, proteins have been identified for juvenile onset glaucoma and late adult onset glaucoma. Further research is under way.
Common genes
The gene for open-angle glaucoma is called GLC1. Of the six known loci for open-angle glaucoma, the first one is GLC1A. The protein at this site is myocilin.
“GLC1A was initially described as juvenile onset glaucoma, with an early age of onset at 5 to 45 years. It is classified as having very high IOP and often demanding surgery to save vision,” said Dr. Samples, a professor of ophthalmology at Oregon Health Sciences University.
The protein for this site, myocilin, is well documented in the literature, he said.
“This is a very interesting protein. One side of it has a myosin-like domain, the kind of myosin found in the motor proteins of skeletal and muscle tissue,” he said.
The other side of the myocilin protein has a mucin layer that surrounds olfactory neurons. In between the two components of the protein is a “zipper-like” structure that allows the protein to interact with itself.
The GLC1A protein has been estimated to account for up to 14% of juvenile onset glaucoma and 1% to 5% of adult onset glaucoma, Dr. Samples said.
Another “classic” open-angle glaucoma protein is GLC1F. The protein is not yet identified; however, it occurs naturally in adults with a later onset than GLC1A. Those carrying the gene GLC1F may develop glaucoma between the ages of 25 and 70.
Indigenous genes
The next defined locus, GLC1B, is less common.
“GLC1B is less frequent. It has been seen in six families with low to moderate levels of IOP,” Dr. Samples said.
Patients from the families studied who carry GLC1B have an early onset and moderately elevated pressures, or normotensive glaucoma. Dr. Samples said these patients have a good response to medication.
GLC1E is another protein that has been identified in families.
“This locus actually has had its protein identified, like GLC1A. The protein is optineurin. Optineurin is bound to chromosome-10 and has a mutation,” Dr. Samples said. This mutation has been carried down through generations in a large British family to produce a manifestation of open-angle glaucoma.
Mary Wirth, MD, and other researchers at Dr. Samples’ center, the Casey Eye Institute in Portland, in conjunction with the National Eye Institute, discovered another hereditary genetic mutation in Greece. This locus is known as GLC1C.
“GLC1C is found on chromosome 3. It has a typical open-angle glaucoma profile, with moderately elevated IOP,” Dr. Samples said.
GLC1C was found in a select group of inhabitants of northern Greece who lived in a contained area.
“This area has remained stable since about 600 B.C.,” he said. “It’s a high mountainous region below Albania. The villagers tend to marry within their group and don’t migrate in and out of the area.”
The population has remained stable at around 300,000 for centuries.
“There has been consanguinity in this area, and linkage disequilibrium has occurred in these people,” Dr. Samples said. Linkage disequilibrium is the occurrence of genes acting together more often than would be expected.
“This association occurs when genes travel closely together through many generations for centuries. It occurs when there is a founder effect and the population is stable,” he said.
This is how the GLC1C gene became indigenous to a select Greek population.
Flushing out genes
In the past few years, Dr. Samples and colleagues have attempted to determine the frequency of mutations of GLC1C from the population by performing fundus and IOP exams and distributing medication.
Dr. Samples urges ophthalmologists to contact him if they treat families of five persons or more with the same glaucomatous traits. These families may help unlock the key to early glaucoma management, or even help eradicate the genetic mutation.
“If you have families with affected individuals, please call or write,” he said. “Once we correct these genes, we may be able to do something about glaucomatous optic neuropathy.”
For Your Information:
- John R. Samples, MD, can be reached at Casey Eye Institute, 3375 SW Terillinger Blvd., Portland, OR 97239; (503) 494-7667; fax: (503) 494-3017; e-mail: samplesj@ohsu.edu.