Mutant gene causes severe kidney disease in infants

Scientists at the University of Michigan Medical School have discovered a previously unknown cause for a severe, early-onset form of kidney disease and renal failure in children: recessive mutations in a gene called phospholipase C epsilon or PLCE1.

Identifying the mutant gene is important to scientists because PLCE1 affects the development of podocytes – specialized cells that play a vital role in the kidney's ability to remove waste products from blood, while retaining important blood proteins.

To parents of infants with inherited PLCE1 mutations, the study is especially significant because it provides the first evidence that some types of a kidney disease called nephrotic syndrome, if diagnosed early in infancy, may be treated successfully in children.

"This is the first report of infants with two mutations in a recessive gene for steroid-resistant nephrotic syndrome who nevertheless responded to steroid treatment," says Friedhelm Hildebrandt, M.D., the U-M's Frederick G L Huetwell Professor for the Cure and Prevention of Birth Defects. "The early onset form of the disease is severe and infants often go into end-stage renal disease within the first year of life. So, until now, most physicians believed there was no point in trying treatment."

The study will be published Nov. 5 in Nature Genetics as an Advance Online Publication, and will be printed in the journal's December 2006 issue.

There are many types and many causes of nephrotic syndrome, but basically it is a disease of the glomerulus, the kidney's main blood filtration unit. There are about one million of these filtration units in each human kidney. As blood flows through a network of tiny capillaries in the glomerulus, excess water, salts and toxic molecules are removed and flushed out in urine, while important blood proteins like albumin are retained in the bloodstream. If the kidney's filtering units don't work properly, nephrotic syndrome develops. Proteins leaking out from the glomerulus are excreted in urine, and body tissues retain too much water, which causes swelling around the eyes and throughout the body.

Some types of nephrotic syndrome can be treated with steroids or other drugs, but steroid-resistant forms of the disease as a rule do not respond to treatment. Untreated nephrotic syndrome often causes severe scarring and a condition called focal segmental glomerulosclerosis (FSGS), which progresses about 50 percent of the time to end-stage kidney disease and renal failure.

PLCE1 is the seventh gene scientists have found to be involved in different types of steroid-resistant nephrotic syndrome, and the second gene that is expressed in podocytes – specialized cells with octopus-like tentacles surrounding the glomerulus.

Podocytes are currently under intensive study, because scientists believe they play a vital role in the blood filtration process. Identifying genes and proteins that are active in podocytes will help scientists understand how they work.