Recent Advances in Research - 1998
From the Foundation
Fighting Blindness Newsletter
by Tom Hoglund
Science Information Manager
[Usher Syndrome Breakthrough]
[Best Disease Gene Discovered]
[Gene Discovery For Age-Related
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Usher Syndrome Breakthrough
In the June 12,1998 issue of Science magazine, a research group
led by Dr. William Kimberling of Boys Town National Research
Hospital in Omaha, Nebraska reported on the discovery of mutations
in a gene causing Usher syndrome type IIa. Usher syndrome is an
autosomal recessive disease that causes moderate to severe hearing
loss and retinal degeneration from retinitis pigmentosa
Explaining the importance of this genetic discovery, Dr. Kimberling
stated, "There are at least nine genes that each cause different forms
of Usher syndrome. Usher syndrome type IIa is the most common
form of the disease accounting for over half of all cases. With this
gene, we can now study its function in vision and hearing. We can
also learn how mutations in the gene cause deaf-blindness. With a
better understanding of the disease process, we can develop effective
treatments. This discovery will help a lot of people with Usher
syndrome." The Foundation is pleased to have supported
this breakthrough. Dr. Kimberling, a recognized expert in Usher
syndrome, received funding for this study through The Foundation's
genetics grant program. Dr. Anand Swaroop, a leading geneticist in
retinal degenerative diseases from the University of Michigan and a
Foundation genetics grantee, also received funding to collaborate on
To find the genes and mutations that cause Usher syndrome and
other retinal degenerative diseases, researchers study DNA obtained
from blood samples of patients and family members with Usher
syndrome. Finding genes that cause autosomal recessive diseases
like Usher syndrome is extremely difficult. Often there are too few
affected family members to compare with unaffected family members.
Usher syndrome is also rare, making it a challenge to find enough
patients to study.
Despite these obstacles, the Usher syndrome IIa gene is now the
second gene scientists have identified for this disease.
In 1995, Dr. Kimberling was part of a collaborative research group,
supported in part by The Foundation, that isolated the gene for Usher
syndrome type Ib. Subsequent research studies have found that this
gene encodes a protein called myosin VIIa. The myosin VIla protein is
found in photoreceptor cells in the retina and in cilia cells in the
cochlea. The cochlea is part of the inner ear. Cilia cells, which look
like tiny fibers of hair, help turn sound waves into electrical impulses
that travel to the brain via the auditory nerve.
Although further study is needed, the myosin VIIa protein appears to
aid in the transport of important substances within these cell types.
Mutations in the myosin VIIa gene produce an abnormal protein that
cannot perform its transport function. As a result, both the cilia and
photoreceptor cells degenerate causing hearing loss and blindness.
Current research is focused on understanding what the myosin VIIa
protein transports. With a more precise understanding of the gene's
normal function, scientists can develop therapies that overcome the
dysfunction resulting from a disease-causing genetic mutation.
This example highlights the critical importance of genetic research in
finding treatments and cures for all retinal degenerative diseases.
However, further progress cannot begin until a disease causing gene
has been identified. It is extremely fortunate that researchers have
now found the gene for the most common form of Usher syndrome.
The Foundation continues to fund the necessary research studies to
find the remaining genes that cause Usher syndrome.
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Best Disease Gene Discovered
On the heels of the Usher discovery, in the July issue of Nature
Genetics, researchers reported on the discovery of mutations in a
gene causing Best disease. Best disease, also known as vitelliform
macular dystrophy, is an autosomal dominant form of macular
degeneration. Although the age of onset can vary, Best disease is
usually diagnosed during childhood or adolescence. Best disease is
distinguished by an abnormally large accumulation of a fatty
substance called lipofuscin that forms beneath the macula. This
accumulation interferes with the function of photoreceptor cells in the
macula causing central vision loss.
Now that researchers have identified the Best disease gene, they can
study the protein it produces to understand its function in the retina.
They can also begin to understand how a genetic mutation results in
the accumulation of lipofuscin. This knowledge will greatly enable
researchers to develop treatments for Best disease. Scientists are
also interested to determine whether the Best disease gene plays a
role in age-related macular degeneration (AMD). Lipofuscin deposits
are common in patients with AMD.
The discovery of the Best disease gene was supported by Merck
Research Laboratories. Merck's participation is a welcome sign that
the pharmaceutical industry is devoting resources to finding
treatments and cures for retinal degenerative diseases.
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Gene Discovery For Age-Related
Yet another genetic discovery was announced by researchers from
Oregon Health Sciences University and Rockefeller University. They
recently mapped a gene causing an autosomal dominant form of age-
related macular degeneration (AMD) to chromosome 1. Gene
mapping is the process of identifying which of the 23 paired
chromosomes contain a gene with disease-causing mutations. This
study, published in the August 1998 issue of Archives of
Ophthalmology, is the first time researchers have identified a form of
AMD exhibiting autosomal dominant inheritance. It is also the first time
researchers have been able to use genetic linkage analysis to map a
gene for AMD.
Genetic linkage analysis is a critical research tool to isolate genes
associated with retinal degenerative diseases. In these studies,
researchers collect DNA blood samples from a large family with retinal
degeneration. Using highly sophisticated technology, geneticists
compare DNA samples from affected and unaffected family members
to locate where the disease-causing gene resides. Once the gene is
mapped to a specific chromosome, geneticists further narrow its
location until the gene is isolated and the disease-causing mutations
Many genes causing retinal degeneration have been identified using
genetic linkage analysis. Unfortunately, owing to the late age of onset
of AMD, there are rarely enough surviving family members to
successfully deploy this research method. However, in this case
clinicians identified an unusually large older-age family with ten
affected by AMD. Dr. Richard Weleber, a coauthor of the study and Principle
Investigator at The Foundation's Research Center at the Oregon Health
Sciences University, received support for this study from The Foundation.
Previous research studies have already provided strong evidence that age-
related macular degeneration (AMD) is a genetically inherited disease. For
instance, a groundbreaking study published in 1997 found that family
members of patients with AMD are more than twice as likely to develop the
disease than those with no prior family history. A more recent study found
that certain common alterations in the APOE gene are significantly
associated with either increased or decreased risk of AMD. (The APOE gene
encodes a protein that transports lipids to maintain and repair nerve cell
membranes.) Scientists are also currently working to determine whether
certain alterations in the ABCR gene are disease-causing mutations or
harmless polymorphisms (variations in the gene's sequence that do not cause
Researchers have also begun candidate gene analysis studies. In candidate
gene analysis studies, researchers first identify genes that are likely
candidates to contain mutations that cause disease. In the case of AMD,
candidate genes are those genes expressed highly in retinal cells and/or
specifically in the macula. Once these genes are identified, researchers then
screen patient blood samples to look for disease-causing mutations in these
Through these efforts and the others listed in this issue of Update, The
Foundation is working to find the genes that cause AMD, Usher syndrome,
and all other retinal degenerative diseases. With recent advances in gene
therapy, the hunt for these genes becomes ever more urgent.
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Date last modified January 1, 1999