This chaperone-like protein, AHSP, was identified in a screen for genes induced by the transcription factor GATA-1, which promotes erythrocyte differentiation. Many genes were induced by GATA-1, but Weiss found AHSP particularly interesting because it was strongly and specifically expressed in RBCs and had no known function. Screens for protein–protein interactions revealed that AHSP bound to α-globin, but not to β-globin or HbA.
AHSP prevented α-globin precipitation in cells and in vitro. In mice lacking AHSP, erythrocytes contained inclusion bodies and turned over more rapidly than in wild-type mice. “The phenotype of the knock-out mice was relatively mild, probably because red cells do a good job of balancing the amount of α- and β-globin they produce,” says Weiss. “So, AHSP is not absolutely essential when things are good, but may become more important when things aren't going so well.”
Thus, AHSP could be a genetic modifier of β-thalassemia. Patients with this disease suffer twofold from a lack of β-globin—they are unable to make enough HbA for good respiratory capacity, and they have an excess of toxic, free α-globin. If a drug could be made to mimic AHSP, it might help offset free α-globin toxicity. This could decrease transfusion requirements in some patients. ▪