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A protein's well-known cousin sheds light on its gout-linked relative
Date:4/8/2013

Johns Hopkins scientists have found out how a gout-linked genetic mutation contributes to the disease: by causing a breakdown in a cellular pump that clears an acidic waste product from the bloodstream. By comparing this protein pump to a related protein involved in cystic fibrosis, the researchers also identified a compound that partially repairs the pump in laboratory tests.

The mutation in question, known as Q141K, results from the simple exchange of one amino acid for another, but it prevents the protein ABCG2 from pumping uric acid waste out of the bloodstream and into urine. A buildup of uric acid in the blood can lead to its crystallization in joints, especially in the foot, causing excruciatingly painful gout.

"The protein where the mutation occurs, ABCG2, is best known for its counterproductive activity in breast cancer patients, where it pumps anti-cancer drugs out of the tumor cells we are trying to kill," says William Guggino, Ph.D., professor and director of the Department of Physiology at the Johns Hopkins University School of Medicine. "In kidney cells, though, ABCG2 is crucial for getting uric acid out of the body. What we figured out is exactly how a gout-causing genetic mutation inhibits ABCG2 function."

A description of the work with Q141K's effects at the cellular level were published online March 14 in the Proceedings of the National Academy of Sciences.

Gout affects 2 to 3 percent of Americans, approximately 6 million people. It usually involves sudden attacks of severe pain, often in the joint at the base of the big toe and frequently in the wee hours of the morning, when body temperature is lowest. It has been nicknamed the "disease of kings," because it usually results from high-purine diets, food that only kings and other noblemen could afford in large quantities in bygone years: red meat, organ meats, oily fishes and some vegetables like asparagus and mushrooms.

While most gout can
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Contact: Catherine Kolf
ckolf@jhmi.edu
443-287-2251
Johns Hopkins Medicine
Source:Eurekalert

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