New gene found for children's lethal kidney disease

August 01, 2003

ANN ARBOR, MI - Scientists at the University of Michigan Medical School have identified a new gene that, when mutated, causes one type of nephronophthisis* or NPHP - a rare disease that leads to kidney failure in infants, children and young adults. NPHP affects one in 1 million people in the United States. It is the most common genetic cause of kidney failure in children and young adults. Other than dialysis or a kidney transplant, there is no treatment and no cure for NPHP.

"At present, we can do the diagnostics and confirm for the patient that this is the disease they have, but we cannot offer any treatment," says Friedhelm Hildebrandt, M.D., the U-M's Frederick G.L. Huetwell Professor for the Cure and Prevention of Birth Defects. "Our only hope is to work out the mechanism to understand where it comes from. Now that we have the gene, at least we know where to start asking questions."

Working with an international team of scientists, Hildebrandt and Edgar A. Otto, Ph.D., a U-M research investigator, found that children who inherit, from both parents, mutated forms of a gene called inversin develop nephronophthisis* type 2, which causes renal failure in infancy. Results from the U-M study were published in the August, 2003 issue of Nature Genetics.

"We found nine distinct recessive mutations in the inversin gene in nine infants with early-onset NPHP from seven different families," Otto says. "We found no inversin mutations in 100 healthy control subjects."

Finding the gene responsible for NPHP2 is especially important, not only because it could lead to a future treatment, but also because of intriguing links between NPHP2 and a life-threatening genetic disorder called polycystic kidney disease or PKD, which affects 500,000 people, mostly adults, in the United States.

"Like polycystic kidney disease, NPHP2 is characterized by extensive kidney scarring," Hildebrandt explains. "Infants with NPHP2 also develop enlarged kidneys with fluid-filled cysts like those seen in adults with PKD. Because the two disorders are so similar, we suspect that NPHP2 may be a kind of bridging disease between nephronophthisis* and polycystic kidney disease."

"Protein expressed by the NPHP2 gene shows up in tiny appendages called cilia found in renal tubular cells in the kidney," Otto says. "Renal tubular cells return important substances, which were removed by the kidney's glomerulus filtering system, back to the bloodstream."

Otto and Hildebrandt found that inversin protein interacts with proteins expressed by nephrocystin - the gene responsible for NPHP type 1, which was discovered by Hildebrandt in 1997. Both proteins are expressed in cilia and interact with beta-tubulin, an important protein found in cilia.

"The new twist is that virtually all proteins known to, if defective, give rise to renal disease in mice and in humans, are expressed in cilia," Hildebrandt says. "Recent studies by other scientists suggest that defective sensing or signaling by cilia cells could cause damage that leads to polycystic kidney disease. So it makes us pretty confident that cilia are central to the pathogenesis of renal cystic disease."

"Cilia seem to be structures designed to sense something," Hildebrandt explains. "They seem to respond to mechanical signals or chemical signals from other cells in ways that regulate cell proliferation and cell development. If these signals are absent or defective, it could cause early developmental problems or it could affect mechanisms that repair damaged kidney cells. More research will be needed to know for sure."

Understanding why and how genetic mutations in NPHP genes lead to renal failure will take many more years of research. But scientists already have some intriguing clues indicating that inversin is required for normal embryonic development. When they removed the inversin gene from embryonic zebrafish, the fish developed severe kidney cysts and heart defects. Injecting the abnormal embryos with inversin messenger RNA from mice restored normal development in the zebrafish.

Studies of embryonic knock-out mice without the inversin gene found that internal organs in 90 percent of the mice were on the wrong side of their bodies - a condition called situs inversus - and 10 percent had serious heart defects. Hildebrandt notes that one of the infants in the U-M study had similar developmental defects.

Hildebrandt and Otto are co-authors on a related study published in the same issue of Nature Genetics describing a different gene, NPHP3, discovered by Heymut Omran, M.D. and other scientists at University Hospital Freiburg in Germany. Mutations in NPHP3 cause another form of the disease, NPHP type 3. Children with NPHP3 appear to have normal kidney function until they are about 10 years old, when they suddenly develop kidney failure.

Papers announcing the discovery of Nephrocystin-4, a gene responsible for another variety of NPHP, type 4, were published simultaneously in 2002 by Otto and Hildebrandt and by Corinne Antignac, M.D., a scientist at Rene Descartes University in Paris.
The U-M study was funded by the German Research Foundation (DFG), the National Institutes of Health and the University of Michigan. Other collaborators from the U-M Medical School were John F. O'Toole, M.D., a resident in internal medicine; research fellows Julia Hoefele, M.D., Rainer Ruf, M.D., and Matthias T. Wolf, M.D., and research assistants Frank Beekmann, Karl S. Hiller, and Adelheid M. Mueller.

*Nephronophthisis is pronounced neph-rono-THI-sis.
Nature Genetics (34) 413-420, August 2003

Additional Contact:
Kara Gavin,, (734) 764-2220

University of Michigan Health System

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