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 Macular Degeneration]

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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 (RP).

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 this study.

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 Macular Degeneration

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 are identified.

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 members 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 disease).

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 genes.

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