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Gene Found for Rare Childhood Kidney Disease

Discovery could lead to new therapies, says expert

SUNDAY, Feb. 3, 2002 (HealthDayNews) -- After years of searching, researchers have identified the gene responsible for an rare, inherited kidney disease that can kill children within days or even hours after birth.

American and Japanese scientists have identified mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene both by using a rat model and by studying the genetic profiles of families with this disease.

Previous studies of 16 families with the condition had already narrowed the search to the sixth human chromosome, but this study pinpointed the mutation to PKHD1.

The gene has already been sequenced by the Human Genome Project, and contains the instructions to produce a newly revealed protein known as fibrocystin. The findings are reported in the March issue of Nature Genetics.

In polycystic kidney disease (PKD), cysts form on the kidneys, then gradually fill with fluid, reducing kidney function. The disease can also interfere with functioning of the liver, heart and blood vessels in the brain.

Roughly 500,000 Americans have PKD. The autosomal recessive form of the disease for which the gene was found -- also called infantile PKD -- is very rare, affecting one in 10,000 children. A child must inherit a copy of the defective gene from both parents. It begins in the earliest months of life, sometimes even in the womb, but some children can live into their teens or 20s.

The disease causes high blood pressure, urinary tract infections and impaired growth. Although those symptoms can be treated, those who have the disease may ultimately require kidney dialysis or transplantation.

Senior investigator Peter Harris, a professor of medicine, biochemistry and molecular biology at the Mayo Clinic in Rochester, Minn., had been studying the autosomal dominant form of the disease that accounts for 90 percent of PKD cases.

When his researchers learned of a breed of rats from Japan with characteristics of the recessive form of the disease, they began to study the animals. Once they found a gene mutation that caused the rats' version of PKD, they turned to the human genome, expecting to find that the same gene was responsible for the disease in people.

Their hunch was correct, and they identified PKHD1 in several human patients with the recessive form of PKD.

Harris says the most immediate implications of these findings are in the potential for new ways to diagnose this disease.

"In the longer term, obviously we hope that a better understanding of what the basic defect is in this disease will enable us to develop a rational therapy for it," says Harris, although he cautions that such a development could be years away.

Dr. Tom Coffman, the chief of nephrology at Duke University Medical Center in Durham, N.C., says the discovery is bound to create a lot of excitement in the field.

"People have been looking for this gene for a while," he says. "It's a real breakthrough in terms of understanding the genetics of polycystic kidney disease."

Coffman, the author of an accompanying commentary in the journal, says the combination of studying families with the disease and animal models of the condition is a "tour de force" of research.

But Coffman cautions that a lot of work remains to be done. "Applications in molecular diagnostics are potentially possible. And certainly now that we know the gene, that really provides a way to direct those sorts of efforts," he says. "But it's going to be tricky."

In terms of new therapies, he says, the use of the rat model with the comparable gene mutation may help to develop and test new therapeutic strategies.

What To Do

For more information on PKD, visit the Web sites for the National Institute for Diabetes, Digestive and Kidney Diseases, the PKD Foundation, or the PKD Access Center.

SOURCES: Interviews with Peter C. Harris, Ph.D., professor of medicine, biochemistry and molecular biology, Mayo Clinic, Rochester, Minn.; Tom Coffman, M.D., chief, Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, N.C.; March 2002 Nature Genetics
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