Clearer mechanism of gout helps drug design

The packing away of Spring Fair food vendors also signifies the end of 2013’s fried Oreo and colossal turkey leg eating spree. Of course, we all know how detrimental those foods are to our health, but few of us are aware of the havoc expensive foods such as fish, mushrooms and asparagus can wreak on our well being, causing a condition characterized by recurrent agonizing pain in the joints.

The “disease of kings” is a glamorous title for the often painful and disconcerting malady more commonly known as gout. Unfortunately for such monarchs (and fortunately for us), scientists are now just beginning to understand the mechanisms that underlie its expression.

Researchers at the Hopkins School of Medicine may have found a genetic mutation link between cystic fibrosis and gout with potential for finding a treatment. The problem lies in a point mutation in the gene known as Q141K, where the amino acid lysine is substituted for a glutamine. This mutation causes a defect in the production of the protein ABCG2, a membrane-associated protein responsible for pumping uric acid waste out of the cell, into the bloodstream, and ultimately out of the body as urine.

This build-up of uric acid causes swelling, not unlike that experienced in arthritis, which is often excruciatingly painful and sometimes balloons to cause massive deformities in the afflicted area. Gout is characterized by symptomatic recurrent swelling in specific joints, most often the first metatarso-phalangeal joint (at the base of the big toe), although such cysts can also form in the kidneys and other joints as well.

It seems as if analogies are the name of the game in the medical world. William Guggino, a professor and chairman in the Department of Physiology at the Hopkins School of Medicine, began this research in 2008 when links were made between the structure of CFTR (cystic fibrosis transmembrane conductance regulator protein) and ABCG2.

“There was a study that was conducted by the NIH that followed about 16,000 people, just collecting clinical values from them,” Guggino said. “Joe Coresh and his group took samples of those patients with high urate values.”

Coresh, a biostatician and epidemiologist at the Bloomberg School of Public Health, suggested that Guggino use the current knowledge on CFTR to help characterize ABCG2.

“If you look for a pattern on the small nuclear polymorphisms, you find that those with high urate concentrations also had the same small nuclear polymorphisms,” Guggino said. “When Joe found this and realized that we were working on a similar protein, he pointed us in the right direction.”

With this knowledge in hand, Guggino explained that their next steps will focus on improving treatments.

“The compounds used in this paper are relatively general,” he siad. “The next step would be to screen for better compounds that are more specific, and to hone in to the ones that affect ABCG2 directly.”

Researchers used techniques known to stabilize the mutant cystic fibrosis protein on mutant ABCG2 proteins and found that such techniques helped to restore ABCG2 function and correct cell membrane placement.

ABCG2 was not entirely unknown to the medical community before Guggino’s work.  In fact, it is rather infamous as the protein that pumps anti-cancer drugs out of breast cancer tumor treatment sites. Despite it’s detrimental effects in the specific field of oncology, researchers are hopeful that further study will help find pave the way for gout treatment options in the future.

Gout accrued the nickname “disease of kings” from the days of old when only wealthy nobleman and their kings could afford to indulge their palates in delectable dishes such as red and organ meats and oily fishes, among other things. Such foods are high in purine, which is metabolized by the body into uric acid and considered a waste product. Unfortunately for those with the means to gorge on such foods, gout is not only a genetic disorder but also induced by dietary habits. Many kings and noblemen suffered as a result since the science was not nearly advanced enough.