Johns Hopkins Gazette: April 3, 1995

Researchers Finally Discover Elusive Kidney Disease Gene

By John Cramer

     Scientists have fully identified and begun exploring the
function of the gene that causes most forms of polycystic kidney
disease, the most common inherited kidney disease, according to a
study by the American PKD1 Consortium, which includes researchers
at the Johns Hopkins Medical Institutions, Integrated Genetics
and Los Alamos National Laboratory.

     Now that researchers know where the gene is and what it
does, the next step, they say, is determining how it works in
order to devise a way to stop it from causing the disease, which
affects 500,000 to 600,000 Americans.

     Their findings are reported in the April 1995 issue of
"Human Molecular Genetics" and were presented at a Renal Cystic
Disease Workshop sponsored by the National Institute of Diabetes
and Digestive and Kidney Diseases on March 31 at the National
Institutes of Health.

     "We're still a very long way off from developing a clinical
therapy, but this is an important step because it gives direction
to scientists. We're not wandering blindly anymore," said Gregory
G. Germino, principal investigator for the Hopkins group and
assistant professor of nephrology. "One of the frustrations of
those of us who care for people with PKD is the lack of therapies
for preventing renal failure. Current treatments are limited to
managing the complications. The major limitation has been our
incomplete understanding of the nature and function of the PKD1

     Katherine W. Klinger, principal investigator for the
Integrated Genetics genomics group and the company's vice
president for science, said "Because this locus is so complex and
duplicated, establishing the correct genomic sequence is key to
understanding the pathogenesis of the disease. Now that the
full-length sequence is identified, sorting out the causative
defects will be our next challenge."

     Last year, scientists in Europe reported partial
identification of the PKD1, or polycystic break point, gene when
they discovered a chromosome break at one end of the gene
responsible for most forms of polycystic kidney disease. This
break disrupted the gene's usual function, allowing the
pinpointing of the site on the gene where the mutation occurs.

     Extending this work, the American consortium, whose work was
funded by the NIDDK, the Marion Merrell Dow/Polycystic Kidney
Research Foundation Research Merit Award and the National Kidney
Foundation, completed research about the gene's location and what
it does by examining its molecular composition. This created a
blueprint for understanding the biology and evolution of the
gene, permitting the cloning and complete sequencing of the gene
to begin analyzing why it mutates and how it functions. 

     Sequencing is a chemical process in which the DNA molecule's
base pairs are taken apart to determine their precise order along
a segment of the molecule. The completion of the sequencing
allows scientists to make the protein that the gene is coded for
and study the protein's normal function and its role in the
disease process.

     The European group identified 40 percent of the gene. The
American consortium identified the remaining 60 percent, found
sequencing differences in the part analyzed by the Europeans, and
found sequences hinting that the gene works through receptors on
kidney cells that bind with an unknown substance in the blood.

     The gene, however, is large and complicated, and extensive
molecular studies are needed. "Once we determine how it
functions, then we can start to explore therapies," Dr. Germino

     Polycystic kidney disease, one of the most common of all
inherited diseases, causes renal failure by middle age in most
sufferers. In some, it also causes cardiovascular complications.

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