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U-M scientists find genetic cause of multiple birth defects affecting kidneys, eyes and other organs


Cilia, hair-like structures on cells, could be the common link to a wide range of congenital diseases

ANN ARBOR, MI – The transition from fertilized egg to newborn baby requires an incredibly complex network of genes, proteins and biochemical signals that scientists are only beginning to understand. Most of the time, development proceeds normally, but just one mutated gene or a missing protein can have a devastating, often lethal, effect. The problem is figuring out which genes and proteins are responsible.

Friedhelm Hildebrandt, M.D., a professor of pediatrics and of human genetics in the University of Michigan Medical School, and his research team have spent 15 years tracking down the genes and proteins responsible for one family of congenital cystic kidney diseases called nephronophthisis or NPHP.

Children with NPHP are born with cysts in their kidneys that eventually lead to renal failure. The disease affects about one new patient per year in 1 million people in the United States, and is the most common genetic cause of kidney failure in infants, children and young adults. There is no cure for the disease. Renal dialysis or kidney transplant are the only treatments.

What U-M scientists have learned from their study of NPHP genes suggests that tiny hair-like projections called cilia, found on the surface of cells throughout the body, could be the key to congenital diseases affecting the kidneys and many other organs.

In a paper to be published online in Nature Genetics on May 7, Hildebrandt describes how his research team discovered a new gene called NPHP6 and found that mutations in this gene cause a rare disorder called Joubert syndrome. Infants with this syndrome are born with NPHP, severe mental retardation and retinitis pigmentosa, an eye disease that causes blindness.

How can a mutation in just one gene lead to simultaneous developmental defects in the kidney, retina and cerebellum of the brain? The answer, according to Hildebrandt, is that all NPHP genes, and possibly genes involved in other types of cystic kidney disease are expressed in cilia, or in supporting structures called basal bodies or centrosomes, from which the cilia grow.

Cilia are found on the surface of nearly every type of cell in animals from zebrafish to humans. Cells depend on these tiny projections to sense motion, light, hormones, odors and many other types of physical and chemical stimuli in their environment.

“Once Mother Nature invented this universal sensory device, she used it over and over in different organisms and different tissues,” Hildebrandt says. “Since cilia are so important to the normal function of most cells in the body, we believe that mutations in genes expressed in these sensory modules could be responsible for a wide range of diseases – including cystic kidney diseases like NPHP, retinitis pigmentosa, liver fibrosis, neural disorders and cardiac defects.

“We knew that defective cilia in kidney tubules were responsible for cystic kidney disease, and that defective cilia in the retina caused retinitis pigmentosa,” Hildebrandt explains. “Our study of patients with Joubert syndrome shows that a mutant form of nephrocystin-6, the ciliary protein encoded by NPHP6, affects cilia on brain neurons in ways that lead to mental retardation. This tells us that cilia are vital for neuronal development, as well as renal and retinal development.”

“NPHP6 is the sixth NPHP gene we have identified so far, and it was the most challenging to find,” says Edgar A. Otto, Ph.D., a U-M research assistant professor in pediatrics and co-first author of the study.

“About 25 percent of all patients with the disease have mutations in the NPHP1 gene, while mutations in other NPHP genes occur in less than 2 percent of patients,” Otto explains. “This makes locating these additional genes very difficult. It took three years of effort by six research fellows using positional cloning to identify the NPHP6 gene on human chromosome 12.”

Tracking down and identifying all the genes involved in nephronophthisis is important, says Hildebrandt, because each gene discovery brings new information about disease pathways that alter normal kidney, eye and brain development.

After finding the NPHP6 gene, Hildebrandt turned to other scientists to quickly determine the gene’s function. He collaborated with Daniel J. Goldman, Ph.D., a U-M professor of biological chemistry, and U-M graduate student Blake Fausett, who “knocked-out” or removed the NPHP6 gene from zebrafish embryos. U-M scientists also worked with Motoyuki Tsuda at Japan’s University of Hyogo who performed the same procedure using a primitive creature called sea squirt.

“All three phenotypes found in patients with Joubert syndrome – renal cysts, retinal defects and cerebellar defects – were found in zebrafish that lacked the NPHP6 gene,” says Otto.

The researchers also found that nephrocystin-6 interacts directly with a transcription factor called ATF4/CREB2. Transcription factors regulate the activity of other genes by turning them on or off.

“NPHP6 appears to increase the activity of this transcription factor,” says Otto. “This is the first connection between a causative gene for nephronophthisis and a mechanism to regulate gene transcription. It’s significant, because it gives us new information about the disease processes involved in NPHP.”

“This finding confirms the unifying theory for renal cystic diseases,” Hildebrandt says. “It appears that all proteins mutated in cystic kidney disease of humans, zebrafish, mice and other vertebrates are expressed in sensory cilia, basal bodies or centrosomes.”

In future research, Hildebrandt’s research team will continue searching for what they believe will be many other genes involved in NPHP.

“The fact that there are so many genes is a mixed blessing,” he says. “It makes them hard to find, but once we have them, we can piece together the full sensory cilium pathway. This will help us understand the pathology of kidney and retinal disease.”

“Knock-out” animals like zebrafish and sea squirt developed for the research study could be used someday to screen drug compounds that might block the effects of defects in nephrocystin-6 or other NPHP-associated proteins, according to Hildebrandt. But he cautions that medical applications are still many years away.

“One has to be cautious, because the remedy for cystic kidney disease could make retinal disease worse,” he says. “The machine is diverse and intricate. It’s like in cancer – you can’t give just one drug for all kinds of cancer. But understanding the common signaling pathway involved will eventually benefit all these diseases.”

Hildebrandt’s research is funded by the National Institutes of Health, the Foundation Fighting Blindness, Research to Prevent Blindness and many other foundations. The University of Michigan has filed patent applications on technology related to this research.

More than 40 scientists from many research institutions collaborated in the study. Other U-M collaborators included research fellows John A. Sayer, M.D., who was co-first author of the paper; John O’Toole, M.D.; Juliana Helou, M.D.; Massimo Attanasio, M.D.; and Boris Utsch, M.D.; in addition to Hemant Khanna, Ph.D; Anand Swaroop, Ph.D.; Hwankyu Lee, Ph.D., Ronald G. Larson, Ph.D., and Susan J. Allen.

Citation: Nature Genetics, DOI: 10.1038/Ng1786

Note for patients and their physicians: For information about participating in U-M studies of genes involved in cystic kidney diseases, please go to
Written by Sally Pobojewski


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