Duke Researchers Find Second Gene Linked to Blood Vessel Disorder
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
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
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-_
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
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
"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
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