Scientists have identified a gene that causes severe glaucoma in children and say the finding could lead to future therapies to treat the disease, which currently has no cure.

Principal investigator Susan Quaggin, chief of nephrology and hypertension at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital, says:

“This work shows us how a genetic mutation causes a severe form of glaucoma called primary congenital glaucoma, which afflicts a significant portion of children enrolled in institutions for the blind worldwide.”

Primary congenital glaucoma is relatively rare; in the general population it is seen in approximately 1 in 10,000 births, according to the American Association for Pediatric Ophthalmology and Strabismus.

The gene called TEK is involved in the development of a vessel in the eye called Schlemm’s canal, which drains fluid from the anterior portion of the eye. In glaucoma, this vessel can be defective or missing, creating pressure buildup that can damage the optic nerve and cause vision loss.

More Than Coincidence

In a previous study, Quaggin showed that deleting the gene in mouse models led to glaucoma, but she didn’t know how mutations impairing the gene affected humans.

After publishing the earlier research, Quaggin met with Terri Young, a pediatric ophthalmologist at the University of Wisconsin-Madison, who had identified mutations in TEK in some of her patients, but didn’t know the significance.

“It was more than coincidental,” Quaggin says, adding that scientists then identified more mutations of the gene in children with primary congenital glaucoma. “It was one of those eureka moments that sometimes happens in science.”

Altogether, scientists found TEK mutations in 10 unrelated families with children who have primary congenital glaucoma. All of the children did not have mutations in other genes known to cause glaucoma.

The TEK gene (also called the TIE2 gene) provides instructions for making a protein called TEK receptor tyrosine kinase. The TEK receptor tyrosine kinase (or TEK receptor) is active (expressed) mainly in endothelial cells, which line the walls of blood vessels.

When the TEK receptor is activated, it triggers a series of chemical signals that facilitates communication between endothelial cells and smooth muscle cells. Layers of smooth muscle cells surround layers of endothelial cells lining the walls of blood vessels.

Communication between these two cell types is necessary to direct angiogenesis and ensure the structure and integrity of blood vessels.

New Therapeutic Target?

Findings made in animal models don’t always translate to patients, but this study shows that TEK mutations identified in children impair the vascular signaling pathway important in Schlemm’s canal formation, just like they do in mice.

“We don’t know how other genes associated with glaucoma cause this disease,” Quaggin says. “With TEK, we know exactly what’s going wrong, which means we’ve identified a pathway that could be a great new therapeutic target for severe glaucoma and even more common forms of the disease.”

Quaggin’s group is developing an eye drop that repairs the TEK pathway to fix the faulty vessel and is also exploring whether TEK pathway mutations play a role in adult-onset glaucoma.

The work was funded by The National Institutes of Health, the Research to Prevent Blindness Lew R. Wasserman Award, the Duke–National University of Singapore Core Grant, the University of Wisconsin Centennial Scholars Award, the March of Dimes Foundation, Howard Hughes Medical Center, Ophthalmic Research Institute of Australia, Channel Seven Children’s Research Foundation, and the National Health and Medical Research Council of Australia.

T. Souma, et al Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity J Clin Invest. 2016. doi:10.1172/JCI85830

Image: Lance Shields/Flickr

For future updates, subscribe via Newsletter here or Twitter