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Howard Hughes Team Links Mutations To Age-Related Macular Degeneration


A team of researchers at Howard Hughes Medical Institute have identified mutations in a gene that may predispose individuals to age-related macular degeneration, the groups said last week.

The mutations affect around 2 percent of patients with the disorder, which is the leading cause of irreversible vision loss in the developed world. Because AMD is so complex — scientists believe the disease may be broken down into as many as 50 distinct diseases — the researchers “don’t understand the molecular mechanisms of the disease very well, and this has limited our ability to develop preventive therapy for it,” according to HHMI investigator Edwin Stone, who is at the University of Iowa Carver College of Medicine.

Stone’s study, which appears in the July 22 New England Journal of Medicine, may enable scientists to build an animal model that could be used to test therapies. “And, if we understood several of the mechanisms, we could potentially divide the patient population into clinically relevant subgroups, so that we could direct specific treatments to those most likely to benefit from them,” Stone said in a statement.

To arrive at their results, the researchers extracted DNA from 402 individuals with AMD and 429 controls and looked for variations in genes that code for fibulins. (The researchers said they chose these genes because the team had earlier linked a mutation in one of these genes, FBLN3, to a disease resembling AMD.)

In the new study, the researchers screened the genes FBLN1, FBLN2, FBLN4, FBLN5, and FBLN6 for variations that could affect the function of various fibulin proteins. They found variations in FBLN1, FBLN2, FBLN4, and FBLN6 that “could have contributed to AMD,” but stressed that these changes “were not statistically significant in terms of their comparative occurrence in AMD patients and healthy controls.”

However, the team found that seven of the 402 of the AMD patients — or 2 percent — had a “different change” in the FBLN5 gene that was not correlated in the control group. Six of these seven changes altered an amino acid in the fibulin 5 protein that has been highly conserved during evolution.

“The most immediate clinical implication of these findings is that if we can use fibulin gene mutations to distinguish a particular group of AMD patients, we could imagine exploring whether they do better with a certain type of treatment than other AMD patients,” Stone said in the statement. “Such distinctions are important, because pharmaceutical companies might already have a treatment that works for perhaps five percent of AMD patients. But if they treated a hundred patients with such a compound, they would conclude that it didn’t work, because it wouldn’t work for ninety-five percent of those patients.”

AMD is a degenerative condition of the macula. It is the most common cause of vision loss in the United States in individuals aged 50 and older, and its prevalence increases with age, according to St. Luke’s Medical Center. The disease is caused by hardening of the arteries that nourish the retina, which deprives the retinal tissue of oxygen and nutrients that it needs to function. As a result, the central vision deteriorates.

AMD affects seven million people in the United States alone. Ophthalmologists diagnose AMD by using vision testing, an Amsler grid test, ophthalmoscopy, fundus photography, and fluorescein angiography.



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