Gene mutation found for eye disease that mimics macular degeneration

University of Michigan Kellogg Eye Center scientists have been studying a family whose members have an eye disease that looks like age-related macular degeneration (AMD), but that has a rarer pattern of inheritance that results in an exceptionally high incidence of the disease among family members in the study.

In the August issue of Investigative Ophthalmology & Visual Science (IOVS), Kellogg scientist Radha Ayyagari, Ph.D., and her collaborators from the U-M and other institutions identify the gene associated with this unusual macular disease. They report on the Tyr141Cys mutation in a gene called RDS.

According to Ayyagari, the marked similarity between AMD and the AMD-like disease will help researchers learn more about the molecular basis of AMD. The findings could have even greater significance because Ayyagari and her colleagues suspect that some individuals with AMD may also harbor the RDS mutation.

AMD is a progressive disease affecting the macula, the area of the retina responsible for central vision that enables us to drive, read, and identify faces. It affects about 1.65 million individuals in this country each year; the first symptoms tend to appear at age 60 or older.

Ayyagari’s group discovered the mutation by studying members of five generations of a large family, known to researchers as SUNY901. The family has a high incidence of a macular disease that resembles AMD, begins at age 50 or older, and has both wet and dry forms, much like AMD.

But in contrast to AMD, it has an autosomal dominant mode of inheritance, which means that the disease can be passed to a child by either parent and that the child of an affected parent has about a 50 percent chance of inheriting the disease.

The family members who are affected by the disease may have symptoms with varying degrees of severity, but the condition frequently results in permanent loss of central vision. Co-author Shahrokh C. Khani, M.D., a U-M-trained ophthalmologist now at State University of New York at Buffalo, examined many members of the SUNY901 family.

“From the clinician’s point of view, the eye disorder in this family looks just like AMD,” says Khani. “It is very similar in clinical behavior, age of onset, and response to treatment; it appears be a kind of mirror of AMD.”

According to Ayyagari, an assistant research scientist in the Department of Ophthalmology and Visual Sciences at the U-M Medical School, the rate at which the SUNY901 family inherited the mutation is one of the most dramatic findings of the research.

“Although AMD has a strong genetic component, we do not see the strong patterns of inheritance we have observed in members of this family,” observes Ayyagari. For example, in the fourth generation, at least 18 of the 23 members inherited the mutation from a carrier or affected parent. The odds of encountering the mutation versus the unaffected gene is closer to three-to-one, rather than the expected one-to-one ratio.

When researchers discovered that the same mutation occurred in a smaller family (BCM-AD033), they realized, after further analysis, that this family and the SUNY901 family must have a common ancestor. Researchers had already studied the genealogy of the larger family and traced its members to a single ancestor who emigrated from Germany to North America. Ayyagari adds that RDS has been screened extensively in populations worldwide; the only two families known to have the rare mutation are the two families described in the paper.

Khani observes that the detailed family history of the SUNY901 family presented genetic researchers with an unusual opportunity.

“When you can study a family with such a well-preserved genealogy, it is easier to get to the root of the disease,” he says. “Most families find it difficult to identify members beyond a first cousin. In this family we think we can identify the first family members to have developed the disease, in the late 1700s.”

Scientists want to understand how the mutation in RDS interferes with the healthy functioning of the eye. They believe that the mutation disrupts the normal structure and function of the RDS protein. As scientists gain more understanding of these processes, they will be able to develop therapies and treatments that counteract or circumvent the effects of the mutations.

In addition to Khani and Ayyagari, coauthors of the paper are: Athanasios J. Karoukis, Rajesh Ambasudhan and Tracy Burch of Kellogg; Joyce E. Young and Richard Stockton of SUNY Buffalo; Richard Alan Lewis of Baylor College of Medicine; Lori S. Sullivan and Stephen P. Daiger of the University of Texas Health Science Center; and Elias Reichel of the New England Eye Center at Tufts University.