DURHAM, N.C. -- Duke University Medical Center researchers have linked a
second gene to a rare bleeding disorder -- a discovery that offers insight
into how blood vessels form and heal in response to injury.
The finding links a previously identified human gene called activin receptor like kinase 1 (ALK1) to the disease hereditary hemorrhagic telangiectasia (HHT), a bleeding disorder that strikes 1 in 40,000 people. Geneticist Doug Marchuk, postdoctoral researcher David Johnson, the study's lead author, and colleagues from Duke and from six other research institutions reported the finding in the June issue of Nature Genetics. The study was funded by the National Institutes of Health, the American Heart Association, and the Baxter Foundation.
HHT, also known as Osler-Weber-Rendu disease, causes tiny veins to fuse into one large mass that can easily be ruptured, causing recurrent bleeding episodes in affected people. In some people, the disease is only a cosmetic problem with tiny red blotches forming on skin or recurring nose bleeds. Others suffer migraine headaches or lesions in the lung or brain that can lead to fatal strokes or aneurysms.
"By studying these genes for rare disorders, we are hoping to open a window into how the body's vascular system operates," Marchuk, assistant professor of genetics, said in an interview. "People often ask, why study genes for a rare disease? First, the disease may be rare, but the genes aren't rare. Everyone has these genes, and we would like to know how they operate normally so we can understand what can go wrong. Second, when it's your family with the disease, it is very important. We would like to be able to offer some hope to these families."
The protein encoded by the ALK1 gene appears to be made almost exclusively in the cells that line blood vessels. While researchers aren't sure of its function, it appears to interact with the potent growth factor, transforming growth factor beta (TGF-_). Researchers are only beginning to unravel how TGF-_ works.
Receptors for TGF-_ are found on the surface of virtually every cell of the body. When
TGF-_ binds to these receptors, signals are relayed inside the cell. The cellular response to TGF-_ depends on the cell type. In some cells, it stimulates growth, while in others it is actually a growth inhibitor. For example, TGF-_ stimulates skin cells to divide, making TGF-_ an excellent wound- healer.
In earlier research, reported in the December 1994 issue of Nature Genetics, Marchuk identified the first gene linked to HHT. This gene, called ENG, is located on chromosome 9 and encodes a protein called endoglin, which also appears to bind TGF-_.
He hypothesizes that both ALK1 and endoglin are TGF-_ receptors specific to the cells lining the blood vessels. They might only be needed if the vessel is injured and needs to be repaired.
"This makes sense with what we know about the disease," Marchuk said. "Children with HHT usually don't show any signs they have the disease. But as they age, and presumably acquire mechanical damage to tiny blood vessels that need to be repaired, the disorder shows up."
Marchuk has shown that families whose disease is linked to defects in the endoglin gene have an increased risk of developing lesions in their lungs that can lead to serious, secondary neurological problems. About 30 percent of people with this form of HHT develop these lung problems.
"We are developing a genetic screen that would identify these people so they can be followed by their doctors more closely for signs of developing lung problems," Marchuk said.
By contrast, people whose disorder is linked to this second gene, ALK1, rarely have lung problems. Like endoglin, this gene provides a blueprint for a protein found almost exclusively in the cells lining blood vessels.
"We realized when we found the first gene that some families were not linked to this gene, meaning HHT really has several forms," Marchuk said in the interview. "Now we have identified a second gene, and we believe there may be a third gene that can cause this disorder."
With two genes now described, Marchuk will begin to piece together what endoglin and ALK1 are doing, whether they interact with each other, and how each normally contributes to the ability of blood vessels to heal in response to injury.
While a treatment based on Marchuk's work may be some years down the road, he emphasizes that for the first 98 years since the disease was described in the medical literature, virtually nothing was known of its underlying cause. Now in two years, Marchuk and his colleagues have linked HHT to two genes and a potent growth factor, TGF-_.
"We've learned a lot in a short space of time," said Marchuk, an advisory board member of the HHT Foundation, a patient advocate group. "Give us a few more years to get this unraveled and we may yet find a clue that could lead to treatment."
Other contributors from Duke include Jonathan Berg, Melanie Baldwin, Carol Gallione, Timothy Stenzel, Marcy Speer, and Margaret Pericak-Vance. Researchers from the University of Edinburgh, Albert Einstein College of Medicine in Bronx, N.Y., University of Newcastle upon Tyne, University of Vermont, University of Toronto, and Henry Ford Hospital in Detroit also contributed.