-Researchers in Cleveland have discovered the first gene associated with the formation of age-related cataracts. EphA2 encodes an enzyme that plays a role in the repair of proteins in the lens of the eye after they become damaged and clump together, according to the investigators.

The work of Bing-Cheng Wang, PhD, and Sudha K. Iyengar, PhD, of the Case Western Reserve University School of Medicine, is part of a large-scale collaborative investigation involving 10 different laboratories from the United States, United Kingdom, and Australia. They published a paper titled “EphA2 is associated with age-related cortical cataract in mice and humans” in the July 31 issue of

PLoS Genetics

.

Expression of the EphA2 protein occurs naturally in humans and mice and decreases with age, providing a possible explanation for cataract formation. The protein, an enzyme called a tyrosine kinase, is responsible for the transfer of phosphate groups to other proteins in the lens, a process known as phosphorylation, which is a common step in cell signaling. When EphA2 is absent, unphosphorylated proteins accumulate and indicate high levels of cellular stress. Researchers believe that these underphosphorylated proteins become sticky, bunch up, and cause damaged proteins to form clusters that damage the structure and impair the clarity of the lens.

“The discovery was serendipitous,” said Dr. Wang, who also is affiliated with MetroHealth Medical Center in Cleveland.

Initially, Dr. Wang’s group was interested in testing the hypothesis that EphA2 was involved in preventing tumor formation. To do so, his lab obtained a line of mice in which the EphA2 gene had been deleted. Supporting the investigators’ hypothesis, the mice without the EphA2 gene became much more susceptible to tumor development, a finding that was reported in the journal

Cancer

.

In addition to the mice having an increased tendency to develop tumors, cataracts formed in the eyes of the mice as they aged. This occurrence was unexpected, Dr. Wang said.

Coincidentally, around the same time, Dr. Iyengar’s group reported in

Proceedings of National Academy of Sciences

that the same gene region was linked to human age-related cataract.

“After many excited phone calls and e-mails, a collaboration was initiated, and the rest was history,” said Dr. Wang, who knew Dr. Iyengar before this research began.

To date, the researchers have identified several specific mutations in the human EphA2 gene that are associated with age-related cataracts and plan to search for additional ones. By better understanding the specific cellular processes by which EphA2 helps maintain lens clarity, they hope to identify the underlying causes for age-related cataracts so that new treatments and ways to prevent them may be developed.

“Our mutant mice will provide a unique platform to find out which specific molecules or cellular processes are affected by EphA2 deletion,” said Dr. Wang. “Meanwhile, studies of human mutant EphA2 also could verify [whether] the same molecules or cellular processes are affected in [the] human lens.”