HBC COMPOUND HETEROZYGOTES [HBC HB RIYADH AND HBC/HB N-BALTIMORE] WITH OPPOSING EFFECTS UPON HBC CRYSTALLIZATION/

Compound heterozygotes of variant haemoglobins (Hbs) with HbC, with or without novel phenotypic changes, have provided insight into the mole cular basis of the interacting haemoglobins and information concerning the role of specific residues in the crystallization of oxy HbC. A hi gh phosphate buffer system has proved useful for studying the effects of variant haemoglobins (naturally coexisting with HbC in the red cell ) on the oxy HbC crystallization process and has led us to conclude th at beta 87 and beta 73 are contact sites of the oxy HbC crystal. We no w present investigations from two HbC compound heterozygotes which exh ibit opposing effects upon HbC crystallization: HbC/Hb N-Baltimore (be ta 95 Lys --> Glu) and HbC/Hb Riyadh (beta 120 Lys-->Asn). The latter inhibits the in vitro crystallization of HbC, explaining the lack of e rythrocyte abnormalities (with the exception of microcytosis) in the d oubly heterozygous infant. In contrast, Hb N-Baltimore accelerates the crystallization of HbC, contributing to multiple abnormalities in red cell morphology, albeit in the absence of morbidity. We conclude that (1) beta 120 and beta 95 are additional contact sites in the crystal, and (2) the HbC/Hb Riyadh haemoglobinopathy demonstrates that crystal lization may not be required for the generation of the observed microc ytosis and increased red cell density in HbC-containing red cells.