Malfunctioning gene is a cause of gout (w/Video)

Jun 19, 2009

Having partnered last year with an international team that surveyed the genomes of 12,000 individuals to find a genetic cause for gout, Johns Hopkins scientists now have shown that the malfunctioning gene they helped uncover can lead to high concentrations of blood urate that forms crystals in joint tissue, causing inflammation and pain — the hallmark of this disease.

The ABCG2 gene, they found, makes a protein that normally transports urate out of the kidney and into urine before the waste product does any harm. In studies using frog egg cells genetically engineered with , the Hopkins researchers established the role of the ABCG2 gene as a cause of , lending credence to suspicions that metabolic deficiencies, in addition to too much rich food and alcohol, are mostly to blame for this painful type of arthritis that affects 3 million Americans. The gene, they believe, may be responsible for some 10 percent of gout in Caucasians.

A report on the research, funded by the National Institutes of Health, was published June 8 in the online Early Edition PNAS.

The research began with a "genome-wide association study" that involved participants of the Artherosclerosis Risk in Communities Study, originally initiated two decades ago to examine the roots of heart disease. Over the course of that research, blood was collected from the study participants and analyzed for a variety of chemical elements, including uric acid. Subjects also reported whether they had ever been diagnosed with gout, enabling researchers to link information from DNA, uric acid levels and gout.

By analyzing associations between blood uric acid levels and genotypes, the researchers identified the gene known as ABCG2 and specifically a certain mutation as a candidate for causing the joint inflammation and pain that are symptoms of gout. Because animal models for gout are not representative of humans — all mammals except for higher primates have an enzyme that efficiently breaks down uric acid — the researchers turned to genetic engineering to figure out just how the human ABCG2 gene might work to regulate uric acid levels, and how its mutation may lead to gout.

First, the team injected both normal and the mutant versions of the human ABCG2 gene into frog eggs which served as the live "factories" for producing the protein made by the gene. A couple of days later, after the egg cells produced lots of ABCG2 protein, the researchers bathed them in a radioactive-tagged uric acid bath.

This video is not supported by your browser at this time.
Michael Kottgen of Johns Hopkins Medicine talks about the collaboration that led to the recent discovery of a gout gene. Credit: Johns Hopkins Medicine

This video is not supported by your browser at this time.
Michael Kottgen of Johns Hopkins Medicine describes gout as a complex disease Credit: Johns Hopkins Medicine

This video is not supported by your browser at this time.
Anna Kottgen of Johns Hopkins Medicine explains genetic risk as it applies to gout Credit: Johns Hopkins Medicine

Using the tag to identify and measure how much urate accumulated in the cells, the investigators then measured how quickly the urate left the cell. Comparing these so-called "efflux rates" to rates in control cells injected with the normal ABCG2, the scientists found that the cells with the mutant ABCG2 protein excreted at a rate just half of normal.

"We were able to show for what we believe is the first time that the ABCG2 protein is vital for transporting urate out of cells,"says Owen Woodward, Ph.D., a postdoctoral fellow in physiology in the Johns Hopkins University School of Medicine.

The researchers further showed that the ABCG2 protein is located in the kidney at a location where urate exretion takes place. They suggest that a lack of efficiency in removing urate from the blood leads to its increased concentration and crystallization. In humans, these crystals get caught in joint tissues, leading to painful inflammation.

"As the first major gene identified to cause gout, we believe that ABCG2 also represents an attractive new drug target," says Michael Kottgen, M.D., a biological chemistry research associate in the Johns Hopkins University School of Medicine.

One strategy is to identify a drug that makes excretion faster and more efficient by activating the "urate transporter" protein.

"Instead of trying to limit urate production — the major current approach to gout treatment — newer treatments could focus on getting urate out of the bloodstream," Kottgen says. "We anticipate that activation of ABCG2 with a drug may help to promote excretion of urate."

"It's exciting that a finding from genome-wide association studies has been directly translated into better understanding physiology and perhaps will help us find better clinical therapies", says Anna Kottgen, M.D., M.P.H., an epidemiologist in the Johns Hopkins University Bloomberg School of Public Health.

Source: Johns Hopkins Medical Institutions

Explore further: Low risk of malignancy for small complex adnexal masses

add to favorites email to friend print save as pdf

Related Stories

New genes linked to gout

Oct 01, 2008

Researchers have identified two new genes – and confirmed the role of a third gene – associated with increased risk of higher levels of uric acid in the blood, which can lead to gout, a common, painful form of arthritis. ...

Got Gout? Duke Leads Study of New Treatment

Sep 02, 2008

(PhysOrg.com) -- A new drug designed to normalize levels of uric acid in the blood appears to be safe and tolerable and may help patients with the painful arthritic condition known as gout better cope with their disease, ...

Recommended for you

Low risk of malignancy for small complex adnexal masses

5 hours ago

(HealthDay)—For older women with small complex adnexal masses, the overall risk of malignancy is low, according to a study published in the December issue of the American Journal of Obstetrics & Gynecology.

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.