March 07, 2003
Gene Mutation Exacerbates Eye Defect in Inherited Glaucoma
While studying mice with a mutant gene whose counterpart causes
inherited glaucoma in humans, researchers have discovered a second gene
mutation that worsens the structural eye defect that causes this type
of glaucoma.
The newly discovered gene mutation affects production of L-DOPA. The
researchers suggest that it might be feasible to prevent glaucoma by
administering L-DOPA, which is used in treating Parkinson's
disease.
“We believed that there could be multiple genetic and/or environmental factors that could affect the course of the disease.”
Simon W. M. John
The researchers, led by Howard Hughes Medical Institute investigator
Simon W.
M. John at The Jackson Laboratory, reported their findings in the
March 7, 2003, issue of the journal Science. John's colleagues
included Richard Libby and Richard Smith of The Jackson Laboratory, and
Frank Gonzalez of the National Cancer Institute.
In their studies in mice, the researchers explored how the absence
of the gene that encodes the protein Cyp1b1 — the same defect that
occurs in humans with primary congenital glaucoma (PCG) — affects
development of glaucoma. In examining the mice, the scientists found
malformations of ocular drainage structures that normally control
pressure as the liquid aqueous humor flows out of the eyeball. These
eye abnormalities are known as anterior segment dysgenesis.
According to Smith, who has treated patients with PCG, the ability
to pinpoint the abnormalities in mice will most likely advance
understanding of how the disease develops in humans. “The
frustrating thing about attempting to understand human PCG is that
there have been very few cases reported in which the patients haven't
already had glaucoma for many years and been subjected to surgery and
multiple medications,” said Smith. “So, by the time we can
examine the human tissue, the anatomic defect is very difficult to
determine.”
According to John, these anatomic abnormalities are an underlying
cause of the severe glaucoma that affects people with PCG. Although the
disorder is relatively uncommon — occurring in about one in 10,000
births in the United States — it can cause devastating consequences,
he said.
“If you have abnormalities or decreased functioning of the
drainage structures, the input of aqueous humor can result in increased
intraocular pressure and the very nasty glaucoma that human infants
suffer,” he said. “This can be a painful condition with
pressures high enough to tear the cornea and risk loss of
vision.”
One puzzle confronting researchers, said John, is that some infants
with the inherited condition can suffer serious glaucoma, while others
either show delayed effects or none at all. “So, although it is
not widely accepted, we believed that there could be multiple genetic
and/or environmental factors that could affect the course of the
disease,” he said. Such factors could interact with one another
to compromise the intricate drainage structures to a greater degree in
some cases than in others, said John.
A clue to one possible genetic factor arose from observations that
albino mice lacking Cyp1b1 appeared to show worse pathology than
pigmented mice. A series of genetic crosses of various mice by Libby
and his colleagues produced strains of mice whose only difference was
the presence or absence of pigmentation. The researchers ultimately
pinpointed the key modifier of severity of glaucoma, showing that in
the Cyp1b1-negative mice it hinged on the status of the gene that
encodes the enzyme tyrosinase. The tyrosinase enzyme is involved in the
pigmentation process as a key catalyst for converting the amino acid
tyrosine to a precursor pigment molecule, L-DOPA.
The researchers also explored how mutations in the gene for
tyrosinase affected mice lacking the FOXC1 gene, which also
causes PCG and other forms of glaucoma in humans. They found that the
tyrosinase-deficient FOXC1 mice also showed more severe
abnormalities in their ocular drainage system.
To determine whether administering L-DOPA might alleviate these
defects, the researchers administered the chemical to the drinking
water of pregnant mice lacking both Cyp1b1 and tyrosinase. They found
that the treatment prevented the severe abnormalities in pups born to
the mice who had been fed L-DOPA.
John noted that another enzyme, tyrosine hydroxylase, is also
involved in L-DOPA production, suggesting yet another biochemical
pathway affecting anterior segment development in the eye and severity
of PCG.
“Together, these findings open a new avenue for investigating
the role of L-DOPA in anterior segment development and glaucoma caused
by various genes,” said John. “Furthermore, identifying
L-DOPA as a key molecule may link the functions of many of the known
genes that cause anterior segment dysgenesis and glaucoma,” he
said. “Most of these known genes can affect tyrosine hydroxylase
in the neural crest cells, from which the relevant anterior segment
structures derive. Therefore, our work provides a conceptual linkage
for anterior segment developmental disorders caused by different genes,
and it provides an important framework for future
experiments.”
While the researchers note that L-DOPA is already used to treat
symptoms of Parkinson's disease, they are cautious about recommending
its use in treating glaucoma. “L-DOPA is a molecule that affects
the nervous system, and we need to proceed very carefully with further
animal and human studies before we will know whether such a treatment
can become a clinical reality,” said John.
It may be the case, said John, that drugs that enhance the enzyme
tyrosinase itself — and not administration of L-DOPA — that will be
more useful as therapeutics. “We are very excited because these
findings open up a new avenue for research on these disorders,”
he said.
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