Mar. 19, 2005 ANN ARBOR, Mich. – Scientists at the University of Michigan Medical School have discovered a gene called NPHP5 and found mutations in this gene that cause a rare genetic disease called Senior-Loken syndrome. Children with this syndrome develop a type of cystic kidney disease called nephronophthisis*, as well as a form of blindness called retinitis pigmentosa.
In both the eye and the kidney, U-M scientists found that mutations in NPHP5 produced defects in hair-like cellular structures called cilia, which serve as sensory devices throughout the body. Researchers are interested in cilia, because they may play an important role in diseases ranging from diabetes to Alzheimer's.
News of the discovery is published in the March 2005 issue of Nature Genetics. Edgar A. Otto, Ph.D., a U-M research investigator, is first author of the paper.
"It seems that defective ciliary proteins can lead to disease in virtually all organ systems," says Friedhelm Hildebrandt, M.D., the U-M's Frederick G.L. Huetwell Professor for the Cure and Prevention of Birth Defects, who directed the research. "Just as defective cilia in kidney tubules underlie kidney disease, defective cilia in the light-sensitive portion of the eye cause retinitis pigmentosa."
For the past 15 years, Hildebrandt and his collaborators have been studying nephronophthisis* (NPHP), a disease that leads to kidney failure in infants, children and young adults. Although rare, NPHP is the most common genetic cause of kidney failure in the first two decades of life. Other than dialysis or a kidney transplant, there is no treatment and no cure for NPHP.
In earlier research, Hildebrandt and coworkers discovered three genes, NPHP1, NPHP2, and NPHP3, mutated forms of which are responsible for three types of nephronophthisis. In 2002, they discovered a fourth gene, NPHP4, simultaneously with another research team in France.
The most recently discovered gene, NPHP5, accounts for a small percentage of nephronophthisis cases, but it plays a central role in retinitis pigmentosa, a type of blindness that sometimes goes hand-in-hand with NPHP. While only about 10 percent of patients with mutated forms of any of the four previously discovered NPHP genes have the related eye disease, all NPHP patients who have mutations in NPHP5 develop retinitis pigmentosa by age three.
What's especially interesting, according to Hildebrandt, is that similar molecular mechanisms appear to cause both blindness and kidney failure. U-M researchers knew from their previous work that the proteins produced by NPHP genes are expressed in the kidneys' primary cilia – hair-like projections extending from the surface of cells lining the kidney tubules.
"When bent by the flow of urine, primary cilia send signals that influence key cellular functions," Hildebrandt says. "Mutations in NPHP genes prevent cilia from functioning properly, causing damage that leads to kidney disease."
These important sensors aren't confined to the kidneys, however. "Sensory cilia are universal devices which can sense very divergent stimuli – such as motion in the kidney, photons in the photoreceptors in the eye, hormones, or scent in the olfactory epithelium," Hildebrandt says. "Whenever Nature needs a device to sense a signal from outside the cell, it seems to be using a cilium.
"Dr. Otto found that the gene product of the NPHP5 gene, which we call nephrocystin-5, directly interacts with calmodulin, which is known to be an important signaling protein in photoreceptors," Hildebrandt adds. "Our collaborators at U-M's Kellogg Eye Center found that nephrocystin-5 is part of a protein complex together with another protein called RGPR. If mutated, the gene for RGPR is a frequent cause of retinitis pigmentosa.
"What was also very striking was that nephrocystin-5, together with calmodulin and RGPR, is expressed in the cilia of kidney epithelial cells, and also in the connecting cilia of photoreceptors," Hildebrandt explains. "In other words, defects in cilia tie together the disease phenotypes of the kidney and the eyes."
Work by other researchers suggests additional connections. "In a disease called Bardet-Biedl Syndrome, patients have a combination of nephronophthisis with retinitis pigmentosa, but also diabetes mellitus, obesity, infertility and mental retardation," says Hildebrandt. "Scientists studying this disease have shown that the genes involved are all expressed in cilia."
There is even evidence that defective ciliated neurons may be involved in Alzheimer's disease, according to Hildebrandt. "Cilia have a scaffold of tubulin, where motor proteins move up and down, carrying cargo. It seems that the proteins involved in nephronophthisis are cargo. Similarly, some of the proteins involved in Alzheimer's also appear to be cargo on cilia."
The research was funded by the National Institutes of Health, the Foundation Fighting Blindness, Research to Prevent Blindness, and the German Research Foundation (DFG).
Anand Swaroop, Ph.D., the Harold F. Falls Collegiate Professor of Ophthalmology and Visual Sciences, and Hemant Khanna, Ph.D., a research fellow in U-M's Kellogg Eye Center collaborated in the study. Other collaborators from the Medical School were Benjamin Margolis, M.D., professor of internal medicine and of biological chemistry; Pamela Raymond, Ph.D., professor of cell and developmental biology; research fellows Massimo Attanasio, M.D., Shuling Fan, Ph.D., Juliana Helou, M.D., John F. O'Toole, M.D., John A. Sayer, Ph.D., and Boris Utsch, M.D.; research assistant Ulla Muerb; research associate Shirley He and graduate student Melissa Tippens.
* Nephronophthisis is pronounced neph-rono-THI-sis.
Citation: Nature Genetics (37) 282-288, March 2005
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