A research team assembled by Integrated Genetics Inc. has identifiedthe gene that causes adult polycystic kidney disease (PKD), acommon inherited disorder that affects more than 500,000 people inthe U.S.

Scientists at Integrated Genetics, of Framingham, Mass., JohnsHopkins Medical Institutions in Baltimore and the Los AlamosNational Laboratory in New Mexico - working under the nameAmerican PKD1 Consortium - sequenced the PKD1 gene after 10years of work.

Although a treatment based on the discovery is still years away,Integrated Genetics President and CEO Elliot Hillback Jr. said adiagnostic to detect the disease may be available in about two years.

Development of a genetic test, Hillback said, depends on progressmade during the next step, which is for the consortium's researchersto determine the gene's function and mutations that result in thedisease.

Hillback said Integrated Genetics, whose business is making genetictests, may try to expedite the development of a diagnostic by buildinga clinical consortium involving other companies and academicinstitutions to help analyze the gene.

"We should not try to keep this knowledge to ourselves," Hillbacksaid. "There's a lot of work to do in determining the mutations andunless one lab puts a lot of money into doing it, it will slow thingsdown."

The patent application for the PKD1 gene lists researchers at bothIntegrated Genetics and Johns Hopkins. In assembling a clinicalconsortium to assist in the ongoing research, Hillback said, non-exclusive licensing agreements would be negotiated withparticipating groups.

"The rates would not be exorbitant," Hillback added, "but we wouldask for a commitment from them to work on the analysis."

As for therapeutic treatments, Hillback said, drugs based on smallmolecule compounds or gene therapy may be options. Cambridge,Mass.-based Genzyme Corp.,parent company of Integrated Genetics, already has a non-exclusivelicense for a potential gene therapy.

Data on identification of the PKD1 gene was expected to bepresented today to participants of the 1995 Renal Cystic DiseaseWorkshop at the National Institute of Diabetes and Digestive andKidney Diseases in Bethesda, Md. A paper describing the discoveryis published in the April issue of Human Molecular Genetics.

Katherine Klinger, Integrated Genetics' vice president, was aprincipal investigator on the research team with Gregory Germino, anassistant professor of nephrology at Johns Hopkins. She explainedthat there are two forms of polycystic kidney disease, adult and theless common recessive form, which manifests itself in infants. Whilethe adult version is present from birth, onset of the disease usuallydoes not occur until middle age.

Klinger said the PKD1 gene is part of a family of genes found onchromosome 16. It is located at 16p13.3 and has 54,000 base pairs.The gene for recessive polycystic kidney disease has been mapped onchromosome 6, but has not been sequenced.

Adult polycystic kidney disease causes cysts to form on the kidney,liver, pancreas and spleen and get progressively larger. The severityof the disease varies. Cysts may form at an early age, but do notaffect most people until they reach about 50 years old.

Another result of the disease is development of cardiovascularproblems, such as aneurysms, which can occur prior to organdamage. Left untreated, people with the disease would die from renalfailure.

Before the American PKD1 Consortium's discovery of the completegene sequence, the European Polycystic Kidney Disease Consortiumreported it identified about one-third of the gene last June. TheEuropean group found the partial sequence while looking for thegene for tuberous sclerosis.

Klinger said sequencing the other two thirds of the PKD1 gene wasdifficult because there were at least three other genes closely relatedto it.

Analyzing the gene, she noted, will involve comparisons betweennormal genes and diseased genes from people afflicted with thedisorder.

Tests Without Treatments?

Klinger said it's difficult to estimate how long it will take to developa genetic test for polycystic kidney disease because it's not knownhow many mutations of the PKD1 gene are involved.

"It could be a few mutations or hundreds," she said. In cystic fibrosis,she added, there are 400 mutations, but tests focus on 32 becausethey are the most prevalent.

Although ethical questions have been raised about using diagnosticsfor genetic diseases without having treatments available, Klinger saida PKD1 test would have several immediate benefits.

In kidney transplants, for example, the best donor is a family memberand a test for PKD1 would insure that one diseased kidney is notswapped for another.

Early detection, Klinger added, also would alert people to the risk ofcardiovascular problems and would permit the use of establishedtherapeutic methods to delay onset of the disease's symptoms.

An unusual aspect of the PKD1 gene discovery, is the identificationof the complete sequence. Most genes being discovered through theHuman Genome Project are only snippets, Klinger observed.

Having a complete sequence not only helps in understanding thedisease better, she said, but also provides insight into how genesequence organization affects such biological activities as geneexpression and gene replication. n

-- Charles Craig

(c) 1997 American Health Consultants. All rights reserved.