Researchers have discovered that genetic mutations underlying two inherited eye disorders arise in different components of a single intracellular signaling pathway that is responsible for development of blood vessels in the eye.
Understanding more about how this pathway functions could provide useful information for the development of drugs to treat the two diseases. That information might also aid in understanding retinal blood vessel disorders associated with diabetes, macular degeneration, and premature birth.
Howard Hughes Medical Institute (HHMI) investigator <<>> at The Johns Hopkins University School of Medicine led the research team, which published its findings in the March 19, 2004, issue of the journal Cell. Co-lead authors of the article were HHMI associate Qiang Xu and HHMI research specialist Yanshu Wang. Other authors are from the National Institute on Deafness and Other Communication Disorders, the University of Utah, and the Wills Eye Hospital in Philadelphia.
The researchers studied two inherited disorders, Norrie disease and familial exudative vitreoretinopathy (FEVR), whose underlying genetic defects were already known, but whose mechanistic relationship was not. Norrie disease, caused by a defect in the gene for the protein Norrin, produces congenital blindness and a progressive deafness due to blood vessel malformation in the inner ear. “Almost certainly the sequence of events within the eye is that there is a problem in vascular development, a compensatory growth of blood vessels, and a leakiness in those blood vessels that leads to scarring and ultimately blindness,” said Nathans. The function of the Norrin protein was unknown before this new work, he said.
The second disorder the researchers studied, FEVR, “tends to be milder and with a range of severity all the way from a modest abnormality of vasculature that does not impair vision at all to a severity of scarring that eliminates vision completely,” said Nathans. FEVR is known to arise from defects in a gene known as Frizzled-4, which codes for a protein receptor (Fz4). Although Nathans and his colleagues had studied the Frizzled-4 gene and the Fz4 protein, they did not know what that external signal was, he said.
The first hints that the two diseases might be functionally related came when the researchers observed intriguing similarities in the blood vessel defects in the two disorders in mice lacking the responsible genes. These vessel pathologies occurred in both the eye and the inner ear.
“While there was a clinical similarity, the two diseases were far from identical, because FEVR patients have a much milder version of the problem,” said Nathans. Also, he said, people with Norrie disease show progressive deafness, while those with FEVR do not. “In speculating about how the pieces of the puzzle of the two diseases might fit together, we thought the idea of a direct relationship seemed kind of crazy — but not too crazy. So, we decided to try a few experiments that might reveal that link. Within a month we had the answer.”