Scientists Find Genetic Cause of Multiple Birth Defects

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."