By Karla Gale

NEW YORK (Reuters Health) – Mutations in the OPTN gene, which encodes for an optic neuropathy inducing protein (optineurin), are responsible for some cases of inherited adult-onset primary open-angle glaucoma. According to the February 8th issue of Science, screening for OPTN mutations may help identify individuals with normal tension glaucoma before optic nerve damage occurs.

Dr. Mansoor Sarfarazi, of the University of Connecticut Health Center in Farmington, and colleagues had previously mapped a glaucoma locus to a five-gene region on chromosome 10p14-p15. The OPTN gene was chosen for investigation because of its known expression in the retina.

The multinational team of investigators studied 54 families with autosomal dominant adult-onset glaucoma; at least one member of each family had normal tension glaucoma. Four sequence alterations in OPTN were identified, one of which was found in seven families. Two additional mutations were found in two other families.

A fourth sequence mutation was detected in glaucoma families, in normal control subjects, and in individuals with sporadic cases of glaucoma. According to the authors, this sequence change "may represent a risk-associated factor or a dominant susceptibility allele."

Dr. Sarfarazi and his colleagues suggest that "mutations in OPTN may be responsible for 16.7% of hereditary forms of normal-tension glaucoma with an additional attributable risk factor of 13.6% in both familial and sporadic cases."

They found that OPTN is expressed in human trabecular meshwork, nonpigmented ciliary epithelium and retina, in addition to several other organs, including the heart, brain, and liver. They believe that optineurin is a secreted protein, based on its expression in the aqueous humor of numerous mammalian species.

As normally expressed, the OPTN gene product is a neuroprotective component of the tumor necrosis factor-alpha (TNF-alpha) signaling pathway, the researchers speculate.

In an interview with Reuters Health, Dr. Sarfarazi pointed out that TNF-alpha is highly upregulated in the eyes of patients with normal-tension and high-tension glaucoma, but not in normal eyes. "TNF-alpha induces the OPTN gene, which serves as a feedback mechanism to reduce the toxicity of the cytokine," he said.

He suggests that further research may demonstrate that optineurin, or one of the proteins with which it normally interacts, such as Huntingtin or transcription factor IIIA, can be used therapeutically for the treatment of glaucoma.

"OPTN may also provide a screening tool for patients at high risk of developing normal-tension glaucoma," Dr. Sarfarazi added. Under normal circumstances, normal-tension glaucoma is not diagnosed until changes to the optic nerve become visible. Prophylactic treatment of such patients by lowering their intraocular pressure could delay the onset of damage to the optic nerve.

Science 2002;295:1077-1079.