Discovery of mutant gene
could make some infant renal disease treatable
Scientists at the U-M 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 podocytesspecialized 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 especially is 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.
"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 Dr. Friedhelm Hildebrandt, 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 was 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 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, it often causes severe scarring and a condition called focal segmental glomerulosclerosis, 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, which are specialized cells with octopus-like tentacles surrounding the glomerulus.
Podocytes currently are 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.
Hildebrandt says most PLCE1 mutations identified apparently prevented mature podocytes from developing normally in the embryo, so defects were present at birth. A milder mutation seemed to delay the onset of the defects until later in life.
U-M scientists used DNA microarrays to analyze blood samples from 26 families around the world who had children diagnosed with steroid-resistant nephrotic syndrome. After eliminating known mutations, the study team was left with DNA from 12 children with the disease. All had inherited recessive PLCE1 mutations from both parents. None of the seven different mutations were present in the 138 control subjects in the study.
All 12 children developed symptoms of nephrotic syndrome before age 4; five progressed to end-stage renal disease before age 5. But surprisingly, two who received early treatment with steroids or cyclosporin A were still alive and healthy, with no symptoms of the disease.
Hildebrandt and his research team couldn't believe children with the most severe form of nephrotic syndrome had been cured of the disease. So they tracked down their physiciansone in Israel and one in Turkeyto confirm the information.
"These children were very fortunate," Hildebrandt says. "Their physicians told us they decided there was nothing to lose by trying a course of treatment."
He and his team now believe there may be a critical time window during which early treatment with steroids can overcome the development defects caused by PLCE1's loss of function, and that early detection of mutated PLCE1 is important.