Globin messenger RNA in hemoglobin H disease.

Functional messenger RNA (mRNA) for human globin synthesis was isolated from reticulocytes of each of two patients with hemoglobin H disease. The RNA was tested for its capacity to direct globin synthesis in a messenger RNA-dependent cell-free system derived from Krebs Type II mouse ascites tumor cells. In each case, hemoglobin H disease mRNA directed the synthesis of a great excess of /3-globin chains relative to a-globin chains of hemoglobin A. The /3/a synthetic ratios obtained in the cell-free system at saturating concentrations of mRNA were >22 and > 15, respectively, for the two hemoglobin H disease mRNA preparations, whereas the /3/a synthetic ratios obtained by incubation of intact reticulocytes from these same patients were 2.6 and 2.8, respectively. The /3/a synthetic ratio obtained in the cell-free system did not vary when lower concentrations of hemoglobin H disease mRNA were used. A marked decrease in the amount of functional aglobin-chain mRNA relative to /3-chain mRNA is therefore associated with the docreased a-chain synthesis observed in hemoglobin H disease. This decrease in a-chain-specific mRNA activity is greater than expected from the /3/a synthetic ratio of intact reticulocytes in hemoglobin H disease. H EMOGLOBIN H DISEASE is a form of a-thalassemia which results from the interaction of two a-thalassemia genes of different severity: the readily detectable a-thalassemia, gene and the barely recognizable a-thalassemia2 (or silent carrier) gene.’ The human a-chain locus is probably duplicated in which case the a-thalassemia2 trait would result from involvement of only one out of four a-chain genes: the a-thalassemia, trait, from involvement of two a-chain genes (in cis): and Hb H disease, from involvement of three out of the four a-chain genes.’ Peripheral blood reticulocytes from patients with hemoglobin H disease in-