To avoid complications from a blood transfusion, recipients must be sure a donors blood matches their own, meaning two main factors must agree: the blood group (A, B or 0) and the Rhesus factor, either positive or negative. Both are antigens expressed on the surface of red blood cells--and if they are different, they can invoke an immune attack. About 85 percent of the population is Rhesus-positive, sometimes making it difficult for Rhesus-negative people in need of transfusions to find a match. Problems can also arise if a Rhesus-negative mother is pregnant with a Rhesus-positive second child. Until now, no one knew the function of the Rhesus factor, which was named after a cross-reacting protein in rhesus monkeys. In todays issue of Nature Genetics, however, scientists from Belgium, France and Italy report that one of its components, RhAG, transports ammonium ions through the cell membrane.

The Rhesus factor consists of several parts, RhD, RhCE and RhAG, and only RhD is missing in Rhesus-negative individuals. The researchers found that RhAG is similar in amino acid sequence to a family of ammonium (NH4+) transporters not found in vertebrates. To test whether RhAG had the same function in humans, they produced the human protein in mutant yeast cells lacking their own ammonium transporters. And indeed the yeast cells survived under conditions when they needed to take up ammonium from the environment. Furthermore, RhAG was able to provide transportation in the opposite direction: it pumped toxic methylammonium as well as excess ammonium out of the cells. The scientists obtained similar results for RhGK, a new Rhesus protein found only in liver cells.

In humans, ammonium is mainly a waste product and becomes toxic at high blood concentrations, so perhaps RhAG serves to help red blood cells take up ammonium from the plasma and transport it to detoxifying organs, such as the liver or kidney. Or maybe ammonium serves as a signaling molecule and the transporter controls the signal. Whatever its exact role, the new results may help scientists to understand Rhesus-deficiency syndrome, a disease in which either RhCE or RhAG are mutated.