Hemoglobin Indianapolis (β112[G14] arginine). An unstable β-chain variant producing the phenotype of severe β-thalassemia

Abstract

Hemoglobin (Hb) Indianapolis is an extremely labile β-chain variant, present in such small amounts that it was undetectable by usual techniques. Clinically, it produces the phenotype of severe β-thalassemia. Biosynthetic studies showed a β:α ratio of 0.5 in reticulocytes and about 1.0 in marrow after a 1-hr incubation. These results, similar to those seen in typical heterozygous β-thalassemia, suggested that β(Indianapolis) was destroyed so rapidly that its net synthesis was essentially zero. To examine the kinetics of globin synthesis, reticulocyte incubations of 1.25-20 min were performed with [3H]leucine. The β(Indianapolis):β(A) ratio at 1.25 min was 0.80 suggesting that β(Indianapolis) was synthesized at a near normal rate. At 20 min, this ratio was 0.46 reflecting rapid turnover of β(Indianapolis). The erythrocyte ghosts from these incubations contained only β(Indianapolis) and α-chains, and the proportion of β(Indianapolis) decreased with time, indicating loss of β(Indianapolis). Pulse-chase studies showed little change in β(A):α ratio and decreasing β(Indianapolis):α and β(Indianapolis:β(A) with time. The half-life of β(Indianapolis) in the soluble hemoglobin was κ 7 min. There was also rapid loss of β(Indianapolis) from the erythrocyte membrane. From these results, it may be inferred that β(Indianapolis) is rapidly precipitated from the soluble cell phase to the membrane, where it is catabolized. Heterozygotes for β0-thalassemia usually have minimal hematologic abnormalities, whereas heterozygotes with β(Indianapolis), having a similar net content of β-chain, have severe disease. The extremely rapid precipitation and catabolism of β(Indianapolis) and the resulting excess of α-chains, both causing membrane damage, may be responsible for the severe clinical manifestations associated with this variant. It seems likely that other, similar disturbances in the primary sequence of globin polypeptide chains may produce clinical findings similar to those seen with hemoglobin Indianapolis and thus produce the phenotype of severe β-thalassemia.