Imbalance in α and β Globin Synthesis Associated with a Hemoglobinopathy

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Abstract
In contrast to findings in the thalasemia syndromes, studies of globin synthesis in subjects with structurally abnormal hemoglobins have generally revealed equal production of α and β polypeptide chains. However, in the present investigation of globin biosynthesis in vitro in blood and marrow from two subjects heterozygous for unstable hemoglobin Leiden, β6 or 7 Glu → O, a significant excess of α-chain production was revealed. A mother and daughter of northern European ancestry with mild compensated hemolytic anemia were found to have 25% hemoglobin Leiden. Increased hemolysis occurred after the ingestion of a sulfonamide and during infections. Normal levels of hemoglobin A2, 3.0 and 2.7%, and hemoglobin F, 0.8 and 0.6%, were found in the two subjects. Similar percentages of the minor hemoglobins were demonstrated in other family members without hemoglobin Leiden. After incubation of peripheral blood with [3H]-leucine, the βA/βLeiden synthesis ratio was 1.3, and the specific activity of βLeiden was 1.3-2 times βA. These results indicate preferential destruction of the unstable hemoglobin Leiden. However, in contrast to previous studies of other unstable hemoglobins, there was excess synthesis of α-chains. The total β/α synthesis ratio was 0.47-0.63 in peripheral blood and 0.82 in marrow. A pool of free α-chains was demonstrated by starch gel electrophoresis and DEAE column chromatography. The synthesis of globin chains was balanced in family members without hemoglobin Leiden. This degree of predominance of α-chain synthesis in subjects with hemoglobin Leiden resembles the findings in heterozygous β-thalassemia. However, the relatively normal hemoglobin content of the cells with this abnormal hemoglobin suggests the possibility of an absolute excess α-chain production in the hemoglobin Leiden syndrome.