The molecular cause of blindness in two congenital diseases, previously thought to be unrelated, has been discovered by researchers at the Johns Hopkins and Howard Hughes Medical Institutes.?
Their experiments showed that defects in proteins required for blood vessel growth in the eyes and ears causes both familial exudative vitreoretinopathy (FEVR) and Norrie's Disease, both of which cause blindness and eventual loss of hearing in the case of the latter.?
The discovery of such a localized signal pathway for angiogenesis (blood vessel growth) is significant in scientists' growing understanding of the phenomenon, which is important in the development of cancer, treating heart attacks and poor limb circulation.
The focus of the researchers' experiments were two proteins called Frizzled-4 and Norrin, which cause FEVR and Norrie Disease, respectively.?
Yanshu Wang, Ph.D., a postdoctoral fellow in the lab of Jeremy Nathans, M.D., Ph.D., created a line of knockout mice for the Frizzled-4 gene roughly four years ago. Wang made the observation that her knockout mice showed problems in blood vessel growth very close to that seen in Norrie's Disease, which is characterized by development problems in eyes and ears.?
This similarity lead Quiang Xu, Ph.D. to begin a series of experiments to determine whether the proteins involved in causing the two diseases interacted in any way.?
The "specificity and high affinity of Norrin-Fz4 binding" lead to a theory that Norrin, a secreted protein, bound Frizzled-4, a receptor protein, and activated a series of intracellular signals that led to angiogenesis, according to their paper "Vascular Development in the Retina and Inner Ear: Control by Norrin and Frizzled-4, a High-Affinity Ligand-Receptor Pair," published in the journal Cell in March of 2004.
Information about these two congenital diseases has been around for over a decade.?
The "Norrie disease gene was found almost 12 years ago, but until now no one had been able to figure out what its product protein did or how it caused the disease.?
Because the proteins involved in the Norrie disease and FEVR are parts of the same processes, these aren't two diseases, they are really two versions of the same disease," said Nathans in a recent Hopkins press release.
These discoveries are significant, according to Dr. Xu, because "understanding more about how this pathway functions could provide useful information for the development of drugs to treat the two diseases, FEVR and Norrie's disease. That information might also aid in understanding other blood vessel disorders associated with diabetes, cancer and heart disease."
Xu explained the thrust of the future research he and his colleagues intend to pursue, saying "now, our study is to pinpoint exactly how Norrin binds to and turns on Frizzled-4, and to find other players in the Frizzled-4-Norrin pathway."
In order to explain the Frizzled-4 and Norrin binding and look for additional members of the pathway, the team intends to utilize protein structure and biochemical tests.
Co-first authors on the Cell paper, Xu and Wang, were assisted by Alain Dabdoub and Chad Woods of the National Institutes of Health (NIH), Philip Smallwood and John Williams of the Department of Molecular Biology and Genetics Howard Hughes Medical Institute, Li Jang and Kang Zhang of the Department of Ophthalmology and Visual Science, University of Utah, as well as William Tasman of the Wills Eye Hospital, Pennsylvania, and Jeremy Nathans of Hopkins Medical and the Howard Hughes Medical Institute.?
Their work was funded by a collection of grants from the Ruth and Milton Steinbach Fund, the NIH, Howard Hughes Medical Institute, the National Eye Institute and the Ronald McDonald House Charities Fund.
