Published: Oct. 5, 2000
Updated: Nov. 3, 2004
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By Duke Medicine News and Communications
PHILADELPHIA, PA -- Researchers at Duke University Medical Center have discovered that a gene on chromosome 4 is responsible for hereditary benign intraepithelial dyskeratosis (HBID), a rare eye disease found predominantly in Native Americans in North Carolina.
The researchers say the gene causes what is known as a "founder's effect," which occurs when a mutation in the genetic makeup of one individual is duplicated in subsequent generations of family members.
HBID is characterized by the formation of benign plaques, or abnormal growths, on the mucosal linings of the eyes and mouth. While it often interferes with normal vision, in some cases it can lead to severe visual impairment. Also, due to the disorder's effects on blood vessels in the mucosal linings, individuals often have red or bloodshot eyes.
Like cancer, HBID is marked by the proliferation of cells, in this case epithelial cells. While this proliferation is not malignant like it is in cancer, lead researcher Dr. Jeffery Vance of Duke believes that the genetic insights gained in rare diseases like HBID can ultimately help in better understanding more common and complex diseases such as cancer.
"Most of what we learn in genetics comes from unique families like these," Vance said. "These insights are like windows of opportunity, allowing us glimpses into the mechanisms underlying biological functions. While we know that the duplication of this gene is the reason for the disease, we still don't know what exactly the gene does. That is the next big step."
In their study, the researchers performed detailed genetic analyses of blood samples collected from more than 350 members of two large families with HBID, and found two distinct markers near the end of chromosome 4 that were common to the 25 family members who exhibited the symptoms of HBID.
"This is an excellent example of the founder's effect, where a mutation occurs in one member of a family that is confined to a certain location by geographic or cultural factors," Vance said. "When that happens, the mutation tends to remain in one place."
Vance prepared the results of the team's study for presentation Thursday at the annual scientific sessions of the American Society for Human Genetics. The study was funded by the National Eye Institute, one of the National Institutes of Health (NIH).
The team, which included Drs. Rand Allingham and Gordon Klintworth of the Duke University Medical Center, was led by Vance, director of the Genomics Research Laboratories at the Duke Center for Human Genetics.
According to Vance, every known case of HBID has either occurred in the North Carolina tribe or can be traced back to it.
Interest in this disease began in the 1960s, with an NIH investigation that ultimately reached no definitive conclusions. By the 1990s, however, as some of the afflicted individuals came to the Duke University Eye Center for treatment, Duke ophthalmologists and geneticists decided to take another look.
For the past three-and-a-half years, the Duke team has described large family pedigrees, collected blood samples and performed the genetic analyses that allowed them to pinpoint the location of the gene with a great deal of confidence, Vance said.
In addition to the genetic component of HBID, researchers have also noted an interesting seasonal aspect to the disorder - during the spring and summer months the disease tends to get worse.
"During the warmer months individuals tend to get more of the growths, and their eyes get redder," Vance explained. "Also, there are more of the white raised patches inside the mouth. So there seems to be an interaction between the genetic component and the environment, and if we could figure out why, we'd have the potential for treating it. Since the epithelium is the outer-most layer of tissue, it is exposed to a lot of things in the environment."
Other members of the Duke team include: Benjamin Seo, Evadnie Rampersaud, Mary Bembe, Dr. Pratap Challa, Tanish Parrish, Dr. John Gilbert and Margaret Pericak-Vance.