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Gene Found for Rare Eye Disease Afflicting Small North Carolina Tribe of American Indians

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Duke Health News 919-660-1306

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.

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