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Polycystic kidney disease

Polycystic kidney disease (PKD) is a progressive, genetic disorder of the kidneys. It occurs in humans and other animals. PKD is characterized by the presence of multiple cysts (polycystic) in both kidneys. The disease can also damage the liver, pancreas and rarely the heart and brain. The two major forms of polycystic kidney disease are distinguished by their patterns of inheritance. more...

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Autosomal dominant polycystic kidney disease (ADPKD) is generally a late onset disorder characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts. Kidney manifestations in this disorder include renal function abnormalities, hypertension, renal pain, and renal insufficiency. Approximately 50% of patients with ADPKD have end-stage renal disease (ESRD) by age 60 years. ADPKD is, however, a systemic disease with cysts in other organs such as the liver, seminal vesicles, pancreas, and arachnoid mater and non-cystic abnormalities such as intracranial aneurysms and dolichoectasias, dilatation of the aortic root and dissection of the thoracic aorta, mitral valve prolapse, and abdominal wall hernias.

Initial human symptoms are hypertension, fatigue and mild pain and urinary tract infections. The disease often leads to chronic renal failure and may result in total loss of kidney function, known as end stage renal disease (ESRD) which requires some form of renal replacement therapy (e.g. dialysis).

Autosomal recessive polycystic kidney disease (ARPKD) is much rarer that ADPKD and is often lethal. The signs and symptoms of the condition are usually apparent at birth or in early infancy.


The disease exists both in an autosomal recessive and an autosomal dominant form. The autosomal dominant form, called ADPKD (autosomal dominant PKD or "Adult-onset PKD") is much more common but less severe. In 85% of patients, ADPKD is caused by mutations in the gene PKD1 (chromosomal locus 16p13.3-p13.1); in 15% of patients mutations in PKD2 (chromosomal locus 4q21-q23) are causative.

The recessive form, called ARPKD (autosomal recessive polycystic kidney disease) is the less common variant, mutations in the PKHD1 (chromosomal locus 6p12.2) cause ARPKD.

A very small number of families with polycystic kidney disease do not have apparent mutations in any of the three known genes. An unidentified gene or genes may also be responsible for this disease.

Polycystic kidney disease is one of the most common inherited disorders caused by mutations in a single gene. It affects about 500,000 people in the United States. The autosomal dominant form of the disease is much more common than the autosomal recessive form. Autosomal dominant polycystic kidney disease affects 1 in 400-1,000 people, while the autosomal recessive type is estimated to occur in 1 in 20,000-40,000 people.


Recent studies in fundamental cell biology of cilia/flagella using experimental model organisms like the green algae Chlamydomonas, the round worm Caenorhabditis elegans and the mouse Mus musculus have shed light on how PKD develops in patients. All cilia and flagella are constructed and maintained, including localizing of protiens inserted into ciliary and flagellar membranes, by the process of intraflagellar transport. Environmental sensing and cellular signaling pathways initiated from proteins inserted into ciliary/flagellar membranes are thought to be critical for normal renal cell development and functioning. Membrane protiens which function in developmental and physiological environmental sensing and intracellular signalling are sorted to and localized to the cilia in renal epithelial cells by intraflagellar transport. These epithelial cells line the lumen of the urinary collecting ducts and sense the flow of urine. Failure in flow-sensing signaling results in programed cell death or apoptosis of these renal epithelial cells producing the characteristc multiple cysts of PKD. PKD may result from mutations of signaling and environmantal sensing protiens, or failure in intraflagellar transport. Two PKD genes, PKD1 and PKD2, encode membrane proteins which localize to a non-motile cilium on the renal tube cell. Polycystin-2 encoded by PKD2 gene is a calcium channel which allows extracellular calcium ions to enter the cell. Polycystin-1, encoded by PKD1 gene, is thought to be associated with polycystin-2 protein and regulate its channel activity. The calcium ions are important cellular messengers which, in turn, trigger complicated biochemical pathways which lead to cell proliferation and differentiation. Malfunctions of polycystin-1 or polycystin-2 proteins, defects in the assembly of the cilium on the renal tube cell, failures in targeting these two proteins to the cilium, and deregulations of calcium signaling all likely cause the occurrence of PKD.


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Megagene unmasked: huge gene leads to many tumors in the kidneys - polycystic kidney disease; includes related article on Janet S. van Aldelsberg's PKD
From Science News, 5/27/95 by Kathleen Fackelmann

Researchers now have a complete picture of the monster gene thought to cause polycystic kidney disease (PKD), an inherited disorder that strikes about 1 in 1,000 people worldwide.

Last year, a team of European investigators nabbed the gene and provided a partial sketch of the sequence of chemical units that go into it. Now, two groups of international investigators have confirmed and extended that work.

"We don't have a magic bullet today," comments Jared J. Grantham, a nephrologist at the University of Kansas Medical Center in Kansas City. "But I'm absolutely convinced that by the turn of the century we're going to have some very effective therapy for PKD." Grantham also serves as chairman of the Polycystic Kidney Research Foundation in Kansas City.

About 600,000 people in the United States have this disease, in which some of the urine-collecting tubules of the kidneys can balloon into tumorlike cysts. These tubules are part of the nephron, the kidney's urine-making workhorse. The cysts can become infected or stop functioning altogether. People who develop renal failure must opt for a kidney transplant or dialysis, a technique in which a machine filters poisons from the blood.

Kidney disease is the dominant feature of this disorder. Yet people with PKD can develop liver cysts and a dangerous pouching, or aneurysm, of a brain artery. Some people with PKD also suffer from high blood pressure.

The story begins with a landmark publication in the June 17, 1994 Cell. Peter C. Harris of the John Radcliffe Hospital in Oxford, England, and a team of European investigators had homed in on the location of a gene that, when mutated, causes about 90 percent of inherited PKD. Other genetic errors cause the remaining cases.

Harris and the European Polycystic Kidney Disease Consortium had identified the gene, called PKD1, on the short arm of chromosome 16, 1 of the 23 pairs of human chromosomes. The team had published a sequence of about 40 percent of the gene's base pairs, the chemical units that make up DNA.

That achievement lit a fire under a team led by nephrologist Gregory G. Germino of the Johns Hopkins University School of Medicine in Baltimore. Germino and his colleagues had been scouring the same neighborhood of chromosome 16 for this gene when the Europeans announced their discovery.

In due course, the Germino group identified the remaining 60 percent of the gene.

When they compared their data to those of Harris' group, they noted a key discrepancy. Germino's team had found an error in the published sequence of the gene.

That misstep, which scientists attribute to the massive size of the gene, had led more than one research team astray (see sidebar). Germino's group detailed their advance at a workshop on March 31 at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md., and in the April Human Molecular Genetics.

Scientists hope such research will help them understand how this gene functions in people with healthy kidneys.

"The disease process helps you identify a normal part of the [kidney's] hardware," Grantham says, adding that the gene could play a role in regulating the growth of the epithelial, or skinlike, cells that make up the wall of the kidney tubule.

Unraveling the gene's normal function may enable scientists to track down what goes wrong in PKD. Genes give a cell the information needed to build proteins from the correct sequence of amino acids. Harris and other investigators have already identified some of the mutations in the PKD1 gene that they believe cause the gene to make an altered version of its protein product. They speculate that the abnormal protein leads to the disease.

Germino's data hint that the defective protein may lace the surface of a tubule's epithelial cells. Such cells may never get the message to stop growing. As they proliferate, the normally hair-thin tubule starts to expand and retain fluid. Eventually, this urine-collecting duct can reach the size of a lemon.

The European announcement inspired another team of researchers who had been doggedly tracking the PKD1 gene.

Sandra Glucksmann of Millennium Pharmaceuticals, Inc., in Cambridge, Mass., and her colleagues also presented their findings at the March workshop. They have put together a more detailed map of the PKD1 gene, including the precise location of the exons, or coding sequences, essential for making the protein.

Her team's map of the gene should speed identification of its protein product, Glucksmann says.

Once she learned about Germino's data, Glucksmann hand-delivered her team's manuscript to the Harvard Square office of Cell. "The competition has been fierce," she notes. The paper, which was accepted in 4 days, appears in the April 21 issue of that journal.

The authors of the Cell report include Glucksmann, Michael C. Schneider of Brigham and Women's Hospital and Harvard Medical School in Boston, and Anna-Maria Frischauf of the Imperial Cancer Research Fund in London.

Harris and his colleagues now have data very similar to those published in the most recent Cell report. Their full description of the PKD1 gene and its predicted protein product appears in the June Nature Genetics.

Such research may lead to a test for PKD. Medical diagnosis of the disorder can be difficult, because symptoms often don't strike until midlife. Even then, only 45 percent of those with the disease go on to suffer renal failure by age 60. For the moment, doctors must ask about family history and then do some detective work in order to identify PKD. If researchers can find the mutations that occur most frequently, however, they may be able to devise a blood test to flag people who have inherited the flawed gene.

Because of the gene's large size, there may be many places in its DNA where flaws can lurk, Schneider says. Multiple mutations would make a simple blood test less likely, he adds. The Polycystic Kidney Research Foundation has set up a consortium to hunt for mutations in this gene, Grantham adds.

A blood test would come in handy for families considering a kidney transplant. In some cases, young persons want to donate a kidney to an older relative who suffers from renal failure. Yet doctors can't always rule out the donor's own risk of developing the disease in the future. With a DNA test, doctors could give potential donors a more definitive indication of risk, Germino says.

Because of the late appearance of symptoms, prenatal diagnosis of fetuses with this flawed gene seems less pressing, Grantham says.

Furthermore, if researchers can figure out how the protein works, they might be able to devise a drug aimed at slowing the progress of PKD. Currently, "there's no pill that will make the cysts go away," Grantham notes. Even treatment that slows cyst growth might make an enormous difference for people whose lives are cut short by this disorder, he notes.

Harris agrees. "We hope we'll be able to understand the basis of this disease," he says. "And from that we hope we'll be able to develop a therapy."

To avoid testing unproven drugs on people, researchers will try to create animals with symptoms similar to those of PKD. By disabling the PKD1 gene in mice, researchers hope to produce rodents with the characteristic cystic kidney tubules.

"That would give us a [more precise] animal model--which we really don't have for this disease," notes Schneider. If they had such polycystic mice, researchers could tinker with various therapies aimed at mitigating or even reversing the course of the disease, he adds.

After more than a decade of research into this black box of a disorder, the discovery of the PKD1 gene represents "an enormous tour de force," Grantham says, noting that researchers in the field now are pursuing a number of intriguing leads.

Finding the PKD1 gene has cleared out an "enormous bottleneck in our understanding of this disease," Germino adds. "There's going to be an explosion in knowledge about PKD over the next 2 to 4 years."

That's not to say that the path ahead will prove smooth. The gene comprises about 14,000 base pairs, making it one of the largest disease-causing genes known to scientists. "It's a big gene," Grantham says. Schneider goes one step further, describing the gene's size as a molecular biologist's "nightmare."

All agree that PKD1 will provide scientists with plenty of challenges in the years ahead.

"I think the complexity of this makes it even more interesting," Schneider says. "We're going to be slogging through this little by little," he says. "I think it's going to be a daunting task for any one group."

COPYRIGHT 1995 Science Service, Inc.
COPYRIGHT 2004 Gale Group

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