Prior to the 1990s, few geneticists were interested in identifying glaucoma genes. After all, the disease had a late age of onset, and they estimated that the heritability of glaucoma was as low as 13%.1

In reality, however, glaucoma is the second most prevalent cause of bilateral blindness in the world, behind diabetes.2 It affects more than 2.2 million people in the United States alonea number projected to increase by 50% by the year 2020.3 It is a complex, heterogeneous group of diseases that cause ganglion cell death and optic neuropathy.

Since the 1990s, discovery of glaucoma genes and the proteins they produce has improved our understanding of the pathophysiology of this complex group of diseases. (See Predicting Glaucoma Based on Proteomics, below.) Once the first locus was discovered in 1993, it sparked an increased interest in genetics. This interest was also sparked by the increased risk (9.2) of patients developing glaucoma themselves.4 Researchers also realized that this knowledge would lead to the development of genetic tests and perhaps new approaches to treatment.

Predicting Glaucoma Based on Proteomics

Proteomics is the study of the proteins that genes produce and how these proteins function. Proteomic profiling studies in glaucoma are currently helping to identify which proteins in the blood, when over- or under-expressed, are associated with the development of various types of glaucoma.

Some of these proteins have been used as a marker for inflammatory disease but also have been found to be associated with glaucoma. One such protein, SAA (serum amyloid A), causes amyloid deposition in tissues. Researchers found that an over-expression of SAA in the trabecular meshwork of glaucoma patients leads to decreased aqueous outflow in humans and increased IOP in mice.42

The future in early glaucoma diagnosis may one day lie in a simple blood test. This test may not look for glaucoma-associated genetic mutations but will test for the presence of proteins which, when over-or under-expressed, are associated with the development of glaucoma. These proteins may appear in the blood years before any structural or functional signs of glaucoma.

Proteomics also opens up the possibility for future prevention of glaucoma by devel-oping drugs to reduce the over-expression or increase the under-expression of these proteins.

Today, geneticists are just beginning to understand that the development of glaucoma in families is variable and depends on a complex interaction of genetics, environmental factors and even the season of the affected individuals birth.5,6 Not only is glaucoma inherited, but risk factors, such as IOP, cup-to-disc ratio and central corneal thickness, are also inherited.7-9 Genetic research may also help unravel the mysteries of those individuals who develop primary glaucoma yet have no family history of the disease.

Here, we will discuss what is currently known about human glaucoma genes.

Primary Open-Angle Glaucoma

The forms of primary open-angle glaucoma (POAG) that may be associated with a genetic
mutation are adult-onset POAG, juvenile-onset POAG (glaucoma before age 40) and low- or normal-tension POAG.

Researchers discovered the first primary open-angle glaucoma locus in 1993.10 The mapping of this first glaucoma locus incited the identification of many other glaucoma gene loci within the next six years. So far, researchers have mapped at least 15 genetic loci for POAG but have actually identified or characterized only a small number of genes.

The first POAG locus to be identified was in pedigrees with juvenile- and adult-onset glaucoma. It was labeled GLC1A and found in the long arm of chromosome 1. (See What is a Locus"?" below.) Eventually, the myocilin, or MYOC, gene was identified at this locus in 1997. 11

What Is a Locus?

The first step to characterizing a gene involves the discovery of specific loci, or sites, on chromosomes that are common to individuals (in a large pedigree) who are affected by a specific disease. These loci are not found in family members who do not have the disease.

A locus for glaucoma consists of (in this order):

The symbol GLC, which is used to identify primary glaucoma loci.
A number that refers to the type of primary glaucoma, namely open-angle glaucoma (1), angle-closure glaucoma (2) and congenital glaucoma (3).
A capital letter that represents the order in which the loci are discovered. Re-searchers replace these symbols with the name for the protein produced once they identify the gene.

For example, GLC1A represents the locus for primary open-angle (1) glaucoma (GLC). The A indicates that this was the first POAG locus that researchers identified.

While researchers have discovered numerous loci for many inherited diseases, they have only characterized a few genes.

MYOC is a protein originally discovered when trabecular meshwork cells were exposed to dexamethasone, resulting in an increased expression of MYOC.12 Mutations in this gene are found in only 3% to 5% of patients who have adult-onset POAG but in as high as 36% of those who have juvenile-onset POAG. 13,14

The second POAG locus to be identified, GLC1B, is mapped to chromosome 2. 15 Most patients who have mutations in this locus have normal-tension glaucoma that develops after age 40.

GLC1C, the third POAG locus to be discovered, is mapped to chromosome 3. It is associated with POAG that is characterized by high intraocular pressure (IOP), late age of onset (ages 38 to 80) and a moderate response to IOP-lowering medications.16,17

GLC1D, the fourth locus to be discovered in the late 1990s, is also associated with a form of adult-onset POAG associated with high IOP. It has been mapped to the long arm of chromosome 8.18

Researchers have not yet identified the genes or proteins produced by mutations in the GLC1B, GLC1C and GLC1D loci.

Here is pigment in the angle in pigment dispersion glaucoma. Researchers mapped the first human pigment dispersion glaucoma locus to chromosome 7 but have not yet identified a gene. So, we cannot currently predict which patients who have pigment dispersion syndrome will develop pigment dispersion glaucoma.

The fifth locus and second gene to be characterized is GLC1E. This gene, called OPTN (which stands for optic neuropathy-inducing protein), is localized to chromosome 10 and codes for the optineurin protein.19 OPTN is found in human trabecular meshwork but is also found in the retina, non-pigmented ciliary epithelium and the brain. Mutations in this gene are associated with adult-onset, low-tension POAG. Since then, however, the literature has been more variable.

Other reports suggest that, depending on ethnicity factors, OPTN may also play a role in high-tension glaucoma and juvenile open-angle glaucoma.20-24 Research has not clearly defined the role OPTN plays in low-tension glaucoma, although it may help protect the ganglion cells from factors that induce apoptosis, or programmed cell death.25

GLC1F, the sixth discovered locus for POAG, maps to the short arm of chromosome 7. It is associated with elevated IOP (22mm Hg to 38mm Hg).26  No gene has yet been identified.

GLC1G, the seventh locus to be discovered, is located on chromosome 5 and on the third adult-onset POAG gene, called WDR36, to be identified.27 It is associated with high- and low-tension forms of glaucoma. Like OPTN, this gene codes for a protein that is present in both ocular and non-ocular tissues. And, like OPTN, this genes role in the pathogenesis of glaucoma is not yet clearly defined.

Most recently, two other primary open-angle glaucoma loci have been identified: GLC1H, on chromosome 2associated with adult-onset glaucomaand GLC1Iassociated with earlier adult onset glaucoma.28 

Besides the open-angle glaucoma genes identified thus far, there are susceptibility genes that may contribute to POAG. These genes affect the clinical course of POAG within an individual. Thus, family members who have the same mutation may have different severity of disease.

Studies are underway to identify the location of these susceptibility genes using sibling pairs among many families. The development of POAG can also vary within families who have the same glaucoma mutations. So-called modifier genes may affect the expression of some glaucoma mutations. The role of modifier genes currently is not well understood.

Pigment Dispersion Syndrome

Pigment dispersion syndrome, usually found in young, myopic Caucasians, is characterized by the release of pigment from the iris. This pigment can coat the lens, lens zonules, trabecular meshwork and corneal endothelium.29 It is usually suspected when an examination turns up endothelial pigment or Krukenbergs spindle.

Transillumination of the pupil before dilation, possibly due to loss of pigment from the iris, is a sign of this syndrome. Gonioscopy reveals dense pigment in the trabecular meshwork.

Gonioscopy may also reveal a concave iris, but ultrasound biomicroscopy (UBM) or another anterior segment imaging device is necessary to confirm this. A concave-shaped iris may result in the iris rubbing against the lens, which in turn releases pigment. Laser iridectomy can help flatten the iris.

Pigmentary dispersion is more prevalent in myopes because these patients have a concavity to their peripheral iris. Pigment dispersion is also seen more in younger patients, as age-related anatomical changes in the eye cause the iris to lift off the lens zonules. (So, as these patients age, less pigment is dispersed because of these anatomical changes.)

Researchers mapped the first human pigment dispersion glaucoma locus to chromosome 7 but have not yet identified a gene.30 So, we cannot currently predict which patients who have pigment dispersion syndrome will develop pigment dispersion glaucoma.

Fast Facts

Transillumination of the pupil before dilation, possibly due to loss of pigment from the iris, is a sign of pigment dispersion syndrome.
Gonioscopy reveal dense pigment in the trabecular network.

Pseudoexfoliation Glaucoma

Pseudoexfoliation, which is the production and accumulation of a fibrillar extracellular whitish material, can occur in ocular and nonocular tissues. The ocular tissues are comprised of the trabecular meshwork, the iris, and most notably, the lens and lens zonules.

This white, flaky material can best be seen on the lens surface through a dilated pupil but in some cases, may also be observable along the pupillary margin of an undilated pupil. Because this material does not represent true exfoliation of the lens capsulenow called capsular delamination of the lens (XS) the process is referred to as pseudoexfoliation.

Pseudoexfoliative syndrome (XFS or PEX) affects several sites in the eye or elsewhere in the body. It leads to pseudoexfoliation glauco- ma in 40% to 50% of patients. 31

Although this condition has a high prevalence in individuals of Scandinavian descent, researchers have not yet mapped any genetic loci, nor have they identified any genes associated with this form of glaucoma.

However, in studies of twins, inheritance in two-generation families increased risk in individuals who had affected relatives, and prevalence differences in specific populations are suggestive of autosomal dominant, X-linked and mitochondrial inheritance. 32-39

Pseudoexfoliation is the production and accumulation of a fibrillar extracellular whitish material in the ocular tissues, which consist of the trabecular meshwork, the iris, and most notably, the lens. These are photos of pseudoexfoliation glaucoma with exfoliative material on the lens (left) and on the lens zonules (right). Because this material does not represent true exfoliation of the lens capsulenow called capsular delamination of the lens (XS) the process is referred to as pseudoexfoliation.

Congenital Glaucoma

This form of glaucoma differs from juvenile-onset glaucoma in that it is an autosomal-recessive inherited, severe form of glaucoma that occurs before age 1. Most cases are bilateral.

Presenting clinical symptoms include epiphora, obvious photophobia and blepharospasm. Examination of the cornea may reveal corneal cloudiness and breaks in Descemets membrane, called Haabs striae, due to corneal stretching from the increased IOP. Also, the corneal diameter increases (megalocornea) so that the eye or eyes may look like marbles.

Gonioscopy reveals malformation of the trabecular meshwork. Mutations in the gene that codes for the CYP1B1 (cytochrome P450 1B1) protein (locus GLC3A on chromosome 2) have been detected in numerous families from different countries where individuals have congenital glaucoma.40

Also, mutations in this gene are responsible for abnormal ocular development. However, most cases are sporadic, with no family history.

Developmental Glaucoma

The developmental glaucomas are diseases in which glaucoma is part of a syndrome. These syndromes include Axenfelds anomaly (anteriorly displaced Schwalbes line with peripheral iris strands), Riegers anomaly (same as Axenfelds but with iris atrophy), aniridia, autosomal-dominant irideogoniodygenesis anomaly and Peters anomaly (corneal opacification, iris adhesions and cataract). 

These congenital anomalies of the anterior segment can subsequently result in the development of glaucoma. There may be malformations evident in other parts of the body as well, such as in the teeth, facial bones and heart.

Mutations in at least four different genes can lead to all these anomalies. These four genes are PITX2, PAX6, FOXC1 and CYP1B1. Mutations in these genes do not necessarily result in the same phenotype. Each is affected by environmental factors as well. For example, mutations in the PITX2 gene can give rise to Axenfelds anomaly, Riegers syndrome or Peters anomaly, all within the same family.41 (See Summary of the Loci and Genes Associated With Various Forms of Glaucoma, above.) 


How to Order Genetic Testing

If your patient has a strong family history of early-onset (juvenile) open-angle glaucoma, you may want to offer genetic testing for mutations or variants in the MYOC gene.
The Carver Nonprofit Genetic Laboratory ( offers testing for some (not all) mutations in the MYOC gene. The turnaround time is eight to ten weeks, and the cost is currently $126.50. Some insurance companies may bear the cost of testing. It is wise to check with genetic counselors in your area who can help educate family members who wish to be tested.
The OcuGene test (In Site Vision) requires swabbing the inner surface of the cheek and sending the sample to the laboratory. This test can only look for one mutation (or variant) in the promoter region of the MYOC gene.
There is controversy concerning the role this mutation plays in the severity of glaucoma. Therefore, until this controversy is resolved, it probably does not make sense to test for this mutation at the current time.

Genetic Testing

As more genes and mutations are identified, should all family members be screened in glaucoma pedigrees to predict the clinical course or severity of the disease? Currently, the answer is no. The relationship between the genetic mutation and resulting disease severity is not yet clear, especially in POAG. So, testing for glaucoma mutations is currently not clinically useful for most forms of glaucoma.

However, you may want to consider offering testing of the MYOC gene to families who have a history of severe early-onset (juvenile) open-angle glaucoma (see How to Order Glaucoma Genetic Testing, above).

As for mass screenings of large populations, we must wait for the discovery of more glaucoma-causing genes and the development of highly sensitive and specific, cost-effective tests that screen for all the mutations in these genes.

The identified genes mentioned here account for only a small number of the overall glaucoma cases we see clinically. In reality, most glaucoma we see is caused by multiple factors. In fact, the interaction of multiple genetic sites likely contributes to disease development.

In the future, the discovery of genes and the proteins they produce will help us differentially diagnose the various forms of glaucoma earlier, predict disease severity, and develop prophylactic treatment.

Presenting clinical symptoms of congenital glaucoma include megalocornea in this patients left eye, which is the diameter increase of the cornea. Microcornea is seen in the right eye.

Dr. Bass is a distinguished teaching professor at the State University of New York State College of Optometry. She is an instructor in the posterior segment disease course in the professional program, and she teaches in the glaucoma, retina and cornea clinic.


Next month: In the final article in this series, Dr. Bass discusses genetic disease of the cornea.


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