Glaucoma is a group of diseases characterized by the triad of elevated intraocular pressure, optic nerve injury, and visual loss. It is very prevalent and is an important cause of blindness in all patient populations. Glaucoma is more common in older patients and in certain ethnic groups. Moreover, a positive family history of glaucoma is a significant risk factor for the disease. The latter facts have led many investigators to propose that at least a subset of glaucoma may have a genetic basis. If this is true, glaucoma should be as amenable to a molecular genetic approach as any of the other disorders already discussed.
A cross section of a human eye. The pressure controlling structures are at the front (right) while the optic nerve exits from the rear (left).
In 1987, we identified a large family with autosomal dominant juvenile glaucoma and have been studying them using linkage analysis. In the spring of 1993 we mapped the disease-causing gene in this family to the long arm of chromosome 1. This was the first time the chromosomal location of a gene for primary open angle glaucoma had been identified. We have since identified additional families affected with the same type of glaucoma and these families were used to narrow the interval containing the gene to less than 3 centimorgans (less than 1/1000th of the total human genome).
In 1997, we used candidate gene analysis to determine that the trabecular meshwork-induced glucocorticoid response protein (TIGR) gene is mutated in 5 families with juvenile onset glaucoma. In addition, mutations within this gene were found to be mutated in a significant portion (at least 3.9%) of a patient population with primary open angle glaucoma. This study was reported in Science. This finding will allow us to identify individuals at risk to develop the disease before visual loss, so that effective sight-saving therapy can be instituted. Furthermore, this discovery lends insight into the molecular cause of at least a portion of glaucoma, which will lead to a greater understanding of the pathogenesis of the disease and the development of more effective therapies.
The optic nerve of a patient with glaucoma viewed from inside the eye. Most of the nerve tissue has been lost leaving only a whitish cup of eyewall behind. The blood vessels that normally exit the center of the nerve are draped along the base of this large cup.
