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Subtle Mutation Linked to Lupus

Lupus, an incurable disease that strikes more than 16,000 Americans a year, causes the body's immune system to turn against itself, creating antibodies that will fight and kill its own cells. In a significant advance, geneticists now say that a tiny change to a single gene contributes to the development of the disease in some people.

Symptoms of lupus can range from achy joints, fever, arthritis, skin rashes, and light sensitivity to life-threatening kidney and blood-clotting problems. Although the disease seems to run in families, researchers have yet to identify the gene or genes that cause it. However, studies of mice with lupuslike symptoms suggested that a gene called PDCD1--which is known to help the body recognize foreign cells--may play a role.

Geneticist Marta Alarcon-Riquelme of Uppsala University in Sweden led an international team of researchers to find out if PDCD1 is also associated with lupus in humans. The team recruited 2510 people of European-American, Mexican, and African-American descent from families with single or multiple cases of lupus, and families with no known history of the disease. The team decoded each person's PDCD1 DNA and found a single mutation--a change to one nucleotide letter of the genetic code--associated with lupus in 12% percent of European-Americans and 7% of Mexicans.

Based on the location of the mutation in the DNA code, researchers believe that the mutation prevents a protein called RUNX1 from attaching to the PDCD1 gene. Because RUNX1 is thought to help cells copy DNA, this disconnect could disrupt immune cells' ability to distinguish the body's own cells from invading microbes by preventing cells from expressing the right amount of PDCD1, the team argues in the 28 October Nature Genetics. This mutation isn't the sole cause of lupus, however; it was also found in 5% of European-Americans and 2% of Mexicans who do not have lupus. And the mutation was almost nonexistent in the African-American population.

"This is a great lead for researchers to work with and now we have a testable hypothesis to pursue," says rheumatologist Paul Utz of Stanford University in California. The next step, Utz says, is to determine whether RUNX1 really does play a role in regulating the PDCD1 gene.

Related sites
Utz home page
Lupus Foundation of America