Molecular Interactions Between Hb α-G Philadelphia, HbC, and HbS: Phenotypic Implications for SC α-G Philadelphia Disease

Abstract

We show here that αG-Phila.2βC2 has an increased rate of crystal nucleation compared to α2 βC2 (HbC). We conclude from this finding that position α68, the mutation site of αG-Phila.2 β2 (HbGPhiladelphia), is a contact site in the crystal of HbC. In addition, that HbS enhances HbC crystallization (additive to the effect of αG-Phila, as shown here) and that αG-Phila. inhibits polymerization of HbS are pathogenically relevant previously known facts. All of these findings help explain the phenotype of an individual simultaneously heterozygous for the βS, βC, and the αG-Phila. genes (SCα-G Philadelphia disease). This disease is characterized by a mild clinical course, abundant circulating intraerythrocytic crystals, and increased folded red cells. This phenotype seems to be the result of increased crystallization and decreased polymerization brought about by the opposite effects of the gene product of the αG-Phila. gene on the βC and βS gene products. Some of the intraerythrocytic crystals in this syndrome are unusually long and thin, resembling sugar canes, unlike those seen in SC disease. The mild clinical course associated with increased crystallization implies that, in SC disease, polymerization of HbS is pathogenically more important than the crystallization induced by βC chains. The SCα-G Philadelphia disease is an example of multiple hemoglobin chain interactions (epistatic effect among globin genes) creating a unique phenotype.

Structure of mutant human carbonmonoxyhemoglobin C (βE6K) at 2.0 Å resolution

“…More recently, we have observed that little or no pathology arises in compound heterozygous patients of HbC, including SC compound heterozygotes, that also express hemoglobins shown to increase the nucleation kinetics of liganded HbC crystallization (Nagel et al, 1993;Lawrence et al, 1997). These studies have also served in the identi®cation of some residues involved in the intermolecular contacts of the crystal (Hirsch et al, 1988(Hirsch et al, , 1998Hirsch, Witkowska et al, 1997;Hirsch, Rybicki et al, 1997;Lin et al, 1989).…”