Secondary gene in severe hemophilia?

One out of every 10,000 males worldwide is born with hemophilia A, an inherited deficiency of the blood-clothing protein called Factor VIII. The disorder, which leaves its victims vulnerable to life-threatening bleeding episodes, is usually treated with Factor VIII isolated from donated blood plasma. But it has long posed a paradox: Some boys with hemophilia A are endangered by any bump or scrape, while others have such mild forms that the disorder goes undetected until they lose their first tooth.

Stylianos E. Antonarakis, a geneticist at Johns Hopkins University School of Medicine in Baltimore, says the explanation may lie in a still-undiscovered secondary gene that controls the operation of the Factor VIII gene. He and his colleagues at Vanderbilt University in Nashville and The Orthopedic Hospital in Los Angeles analyzed mutations in the Factor VIII genes of 30 patients with severe hemophilia A and 17 patients with milder forms of the disorder. They detected mutations in the Factor VIII genes of all but one of the patients with mild hemophilia, but could locate such defects in only 53 percent of those with severe hemophilia.

"Something else besides a defect in the Factor VIII gene is causing severe hemophilia A," Antonarakis concludes. The researchers, whose findings are scheduled to appear in the Aug. 15 Proceedings of the National Academy of Sciences, are now searching for an adjacent gene that could turn the Factor VIII gene on and off. Antonarakis proposes that this regulatory gene may be defective in patients with severe hemophilia A, preventing them from producing any Factor VIII. Even though the Factor VIII gene itself is defective in patients with milder forms of the disorder, he says, they can still produce some partially active Factor VIII.

"The take-home message is: When you find the gene responsible for a disorder, you aren't always finished," Antonarakis says.