In contrast to findings in the thalasemia syndromes, studies of
globin synthesis in subjects with structurally
abnormal hemoglobins have generally revealed equal production of alpha and beta
polypeptide chains. However, in the present investigation of
globin biosynthesis in vitro in blood and marrow from two subjects heterozygous for unstable
hemoglobin Leiden, beta6 or 7 Glu --> O, a significant excess of alpha-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 [(3)H]-
leucine, the beta(A)/beta(Leiden) synthesis ratio was 1.3, and the specific activity of beta(Leiden) was 1.3-2 times beta(A). 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 alpha-chains. The total beta/alpha synthesis ratio was 0.47-0.63 in peripheral blood and 0.82 in marrow. A pool of free alpha-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 alpha-chain synthesis in subjects with
hemoglobin Leiden resembles the findings in heterozygous
beta-thalassemia. However, the relatively normal
hemoglobin content of the cells with this abnormal
hemoglobin suggests the possibility of an absolute excess alpha-chain production in the
hemoglobin Leiden syndrome.