Secrets of The Cilia: Kidney disease and blindness share common genetic
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.