Under Pressure: Mutations in mice could explain how loose pigment molecules spur glaucoma (Glaucoma)
Authors: Seydel Caroline 
Published: August 2003

Excessive pressure within the eye causes glaucoma, the leading cause of blindness worldwide. Some evidence suggests that genes contribute to the disease, but few have been identified. Now researchers who study glaucoma in mice have fingered two suspect genes--at least for one form of the disease.

In healthy eyes, fluid flows through a chamber between the cornea and the lens. A filter strains debris out of this fluid, and when the filter gets clogged, glaucoma results: Pressure builds inside the eye and eventually damages the cells that connect the retina with the brain, causing blindness. In some people, cells in the iris release pigment molecules that can obstruct the filter and cause a form of the disease called pigmentary glaucoma. Fierce disease strikes people in their 20s or 30s; others suffer from a slower progressing version that becomes evident in old age. If clinicians can't detect the offending pigment molecules, they might mistake pigmentary glaucoma for a more common form of glaucoma in which the filter gradually deteriorates with age.

To track down genes involved in pigmentary glaucoma, researchers use a strain of mice that develops a similar disorder. Preliminary analyses implicated two gene culprits: one on chromosome 6 that causes the pigment molecules to loosen around the iris, and one on chromosome 4 that causes the iris to thin. Anderson and colleagues mated the mutant mice with healthy ones to find exactly where the defective genes lay. They analyzed the offspring of a parent with two copies of chromosome 6 that carried the mutation mated with a heterozygous parent, which had one mutant and one normal chromosome. Because the two copies of each parent's chromosomes exchange genetic material during sperm or egg formation, heterozygous parents passed to each offspring a slightly different combination of genes on chromosome 6. By identifying which part of the mutated chromosome was always present in the mice with glaucoma, the researchers narrowed their search to a single candidate gene, called
Gpnmb
. In a similar manner, they identified
Tyrp1
on chromosome 4 as the cause of iris thinning.

Although not much is known about either gene, previous work showed that
Tyrp1
stabilizes an enzyme called tyrosinase, the rate-limiting enzyme for synthesizing melanin, a pigment found in the eye, among other places.
Gpnmb
, meanwhile, turns on in pigment-producing cells. The researchers suggest a possible mechanism by which the mutations might cause glaucoma. In this scenario, specialized structures called melanosomes within pigment-producing cells in the iris break down, releasing toxic pigments or pigment intermediates that poison the cell. When the cell dies, it breaks open and releases the noxious molecules, which then circulate around the eye and damage cells in the filtering organ. If the process occurs in people, researchers might one day target the pigment-producing pathway to prevent disease. In the meantime, the new findings in mice hint at mutations to seek in genetic studies of human glaucoma.

--Caroline Seydel

M. G. Anderson, R. S. Smith, N. L. Hawes, A. Zabaleta, B. Chang, J. L. Wiggs, S. W. John, Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice.
Nat. Genet.
30
, 81-85 (2002).
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