Gene for rare syndrome
linked to inherited glaucoma
BY WILLIAM A. WELLS
Scientists at Stanford and
at the University of Michigan have identified a gene
involved in some cases of inherited glaucoma. The same
gene, called LMX1B, is responsible for a rare inherited
disease called nail-patella syndrome, the researchers
found.
People with nail-patella
syndrome have malformed fingernails, toenails, kneecaps
and elbows. A significant number of them also have
glaucoma. The new findings confirm the researchers'
earlier proposal that the two sets of symptoms in these
patients spring from the same genetic defect, said Dr.
Douglas Vollrath, assistant professor of genetics.
Vollrath is the first author of a research paper
describing the new findings in the July issue of Human
Molecular Genetics.
Glaucoma is the second
leading cause of blindness worldwide. In the United
States it affects more than 2.5 million people, half of
whom do not know they have the disease. Increased
pressure in the eye is thought to destroy nerve cells in
the eye, leading to glaucoma's characteristic patterns of
vision loss. Although it appears that no single gene
defect is responsible for most cases of glaucoma,
scientists suspect that the disease usually is spurred by
genetic components in addition to environmental effects.
"Glaucoma is an
important health problem, so any gene related to it is
important," Vollrath said.
His collaborators in the
newly published work included two researchers from the
University of Michigan, Ann Arbor: Julia Richards,
associate professor of epidemiology; and Dr. Paul
Lichter, professor and chair of ophthalmology. Also
participating were Mark Clough and Iain McIntosh from
Johns Hopkins and technicians Virna Jaramillo-Babb from
Stanford and Kathleen Scott from Michigan.
Physical defects
associated with nail-patella syndrome vary. The skeletal
abnormalities, usually recognizable at birth, can be
severe or mild. Some patients also have kidney defects.
The more severe kidney defects become apparent in early
childhood, but lesser defects may not appear until late
in life. Some patients with the syndrome develop glaucoma
later in life, and others never develop it at all.
This variability suggests
that the new genetic research may have implications
extending beyond people with nail-patella syndrome.
"NPS [nail-patella syndrome] is not a really common
disease, but we're interested to see if the same gene is
involved in other forms of glaucoma, affecting people
without other signs of NPS," Vollrath said.
"Perhaps the syndrome is so variable that patients
with defects in the LMX1B gene could just develop
glaucoma."
If LMX1B is involved in a
large number of glaucoma cases, testing for the defective
gene in families with a history of glaucoma would be
warranted, he said. "There is no cure for glaucoma,
but there are treatments that will slow things down
considerably," Vollrath said. For example, surgeons
can pierce the eye with a laser to relieve the pressure.
In their study, the
Stanford and Michigan researchers focused on four
unrelated, extended families more than 120 individuals
altogether. They were able to obtain blood samples from
48 of the individuals, 31 of whom had nail-patella
syndrome. After extracting DNA from the blood, the
researchers isolated the LMX1B gene and determined the
sequence of this stretch of DNA.
A normal LMX1B gene
carries the blueprint for producing a functioning
transcription factor a protein that turns on the
production of other proteins. Vollrath's team found that
in all 31 of the people with nail-patella syndrome, the
LMX1B gene was mutated such that it would produce a
nonfunctional protein. Among the 31 known to have a
mutated gene, 16 also had glaucoma. Since the chances of
developing glaucoma increase with age, some of the
remaining individuals may get glaucoma in the future,
Vollrath noted.
Other research groups also
have linked the syndrome with the gene, identifying LMX1B
as the candidate NPS gene in papers in the May 1998 issue
of Nature Genetics. The families in their studies did
not, however, show glaucoma, so these researchers could
not make the link to this part of the syndrome. (The
groups were led by Brendan Lee of Baylor College of
Medicine, in Houston, and Randy Johnson of the University
of Texas M.D. Anderson Cancer Center, also in Houston.)
"It was only recently
hypothesized by my colleagues at the University of
Michigan that the glaucoma seen in NPS patients was
part of the syndrome," Vollrath said.
He offered one possible
explanation for the difficulty of recognizing that
connection: "People with NPS get the severe skeletal
defects recognized and fixed very early, and when they
get glaucoma they just don't connect it to the NPS. And
the people who are treating them later in life are
ophthalmologists who may not even be told about the
orthopedic problems their patients had corrected in
childhood."
The identification of
LMX1B as the disease gene explains some of the physical
defects associated with nail-patella syndrome. The
protein normally encoded by the LMX1B gene is known to
direct the development of structures on the top of the
feet and the back of the hands. For example, in mice with
the mutated LMX1B, the nails can be transformed into a
copy of the other side of the limbs the foot pads.
But the functions of LMX1B
in other parts of the body, such as the kidneys or the
eyes, are less clear.
Funding for the newly
reported research came from the National Eye Institute,
the Glaucoma Research Foundation, the Helen Van Arnam
Glaucoma Research Fund, Research to Prevent Blindness,
and the March of Dimes Birth Defects Foundation. SR
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