Reciprocal relationship of hemoglobins A2 and F in beta chain thalassemias, a key to the genetic control of hemoglobin F.

By WOLF W. ZUELZER, ABNER R. ROBINSON AND CLIFFORD R. Booian T HE EXISTENCE of more than one kind of gene capable of producing the stigmata of thalassemia was first suggested’ as a possible explanation for the surprisingly wide spectrum of hematologic phenotypes observed in syndromes thought to result from the combination of a gene for thalassemia with a gene for one of the abnormal hemoglobins such as hemoglobin S or hemoglobin C.23 The idea seemed plausible that several different genes might bring about the picture of thalassemia when present in the simple heterozygous state but might act in quite different ways in the presence of another abnormal gene affecting the composition or rate of production of hemoglobin. This hypothesis was carried a significant step farther by Ingram and Stretton4 who proposed the concept that thalassemia is a molecular abnormality of hemoglobin comparable to other hemoglobinopathies in that the mutant gene causes an amino acid substitution within the molecule but more difficult to recognize because the substitution, in the case of thalassemia, does not happen to produce a change in the net electrical charge and is therefore not manifested by an altered electrophore ic behavior. The hemoglobin molecule is now thought to be composed of two pairs of polypeptide chains, in the case of hemoglobin A two a and two $ chains5 whose production is assumed to be under the control of two corresponding