If two people have the same genetic disease, why would
one person go blind in childhood but the
other later in life or not at all? For a group of genetic
diseases — so-called ciliary diseases that include
Bardet-Biedl, Meckel-Gruber and Joubert syndromes —
the answer lies in one gene that is already
linked to two of these diseases and also seems to increase
the risk of progressive blindness in
patients with other ciliary diseases. The findings were
published online this month by Nature Genetics.
We are limited in our ability to predict how seriously
a genetic disease will affect individual
people, even when changes in specific genes have been
identified and tied to particular diseases, says
Nicolas Katsanis, an associate professor of
ophthalmology and molecular biology and
genetics at the
Johns Hopkins School of Medicine
McKusick-Nathans Institute of Genetic Medicine. "In the
same way
that no two people get exactly the same cancer even though
they might carry the same genetic
alterations, we know little about how one individual's
disease will interact in the context of their other
genes," he said.
One major obstacle to accurately predicting how a
disease plays out in individual patients,
Katsanis says, is our poor understanding of "second site"
changes in DNA. These so-called modifiers
are alterations in other genes that can affect the
functions of the genes that contribute directly to a
given disease.
"Every disease can be considered complex because of
modifiers," Katsanis said. "And we know
very little about modifiers, what they are and how they
affect disease progression. In the case of
ciliary diseases where there is a risk of retinal
degeneration and blindness, we want to be able to use a
person's genetic information to predict whether or not he
or she will go blind and how quickly."
To identify modifiers of ciliary diseases, the team of
scientists examined DNA from patients of
northern European descent and from their parents and looked
for common changes in the RPGRIP1L
gene, which already was known to be defective in some but
not all ciliary diseases. Although the
frequency of any given change in DNA sequence was rare,
several changes appeared only in patients
with ciliary disease and not in healthy people, while some
changes appeared more frequently in patients
than in healthy people. One particular change in the
RPGRIP1L gene, called A229T, was seen frequently
in DNA from patients who had lost some vision but was
absent in DNA from patients who had not lost
vision.
As individual changes in single genes are difficult to
study in people, the team turned to fish to
learn how the A229T change in the RPGRIP1L gene affects
cells. Like humans, fish have a gene very
similar to RPGRIP1L. In addition, fish are transparent in
their early stages of development, a
characteristic that makes it easier to see how individual
changes in genes can affect cellular function,
structure or development. When the researchers reduced the
amount of RPGRIP1L in fish, the animals
developed short and stunted body structures and abnormal
tails. When normal RPGRIP1L was added
back into these same fish, the fish developed more normal
body lengths and tails. However, when
RPGRIP1L with the A229T change was added back to the fish,
they remained short and stunted. So
the researchers concluded that the A229T change must
prevent RPGRIP1L from working properly.
The team then investigated why the A229T change in
RPGRIP1L might lead to retinal
degeneration and blindness in people. To do this, they
looked for other proteins that interact with the
RPGRIP1L protein by fishing the protein out of eye cells
and examining what was stuck to it. They
found one protein that stuck to RPGRIP1L but did not stick
to RPGRIP1L with the A229T change. This
protein interaction must be important for retinal function,
they concluded, and loss of this interaction
may explain how the A229T change in the RPGRIP1L gene
increases the risk for retinal degeneration in
patients with ciliary diseases caused by other genes.
Ciliary diseases can cause a variety of symptoms in
patients, including kidney failure, nervous
system defects, extra fingers and toes, and progressive
blindness. According to Katsanis, whether a
patient goes blind depends on modifiers like A229T. "A229T
increases one's risk 10 percent to go
blind," Katsanis said. "But it's only one single genetic
change of many possible. Now we want to collect
all modifier information so we can develop specific drug
information and specific treatment regimens."
This work was funded by the National Eye Institute;
National Institute of Child Health and
Development; National Institute of Diabetes, Digestive and
Kidney Disorders; Intramural Program of
the National Eye Institute; Macular Vision Research
Foundation; Foundation for Fighting Blindness;
Foundation for Fighting Blindness Canada; Le Fonds de la
recherche en sante du Quebec; Research to
Prevent Blindness; Harold Falls Collegiate Professorship;
Midwest Eye Banks and Transplantation
Center; Searle Scholars Program; UK Medical Research
Council; NIHR Biomedical Research Centre for
Ophthalmology; EU-GENORET Grant; Howard Hughes Medical
Institute; and Doris Duke Distinguished
Clinical Scientist Award.
In addition to Katsanis, authors of this paper from
Johns Hopkins are Erica E. Davis, Perciliz L.
Tan and Michael A. Beer, all of the School of Medicine.
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