Molecular interactions between Hb alpha-G Philadelphia, HbC, and HbS: phenotypic implications for SC alpha-G Philadelphia disease.
We show here that alpha2(G-Phila.) beta2(C) has an increased rate of crystal nucleation compared to alpha2 beta2(C) (HbC). We conclude from this finding that position alpha68, the mutation site of alpha2(G-Phila.) beta2 (HbG(Philadelphia)), is a contact site in the crystal of HbC. In addition, that HbS enhances HbC crystallization (additive to the effect of alpha(G-Phila.) as shown here) and that alpha(G-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 betaS, betaC, and the alpha(G-Phila.) genes (SC alpha-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 alpha(G-Phila.) gene on the betaC and betaS 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 betaC chains. The SC alpha-G Philadelphia disease is an example of multiple hemoglobin chain interactions (epistatic effect among globin genes) creating a unique phenotype.
Lawrence
C
C
Division of Hematology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
Hirsch
R E
RE
Fataliev
N A
NA
Patel
S
S
Fabry
M E
ME
Nagel
R L
RL
D000328:Adult; D001797:Blood Protein Electrophoresis; D003460:Crystallization; D004913:Erythrocytes, Abnormal / Q000737:chemistry / Q000648:ultrastructure*; D005260:Female; D006444:Hemoglobin C / Q000737:chemistry* / Q000235:genetics; D006451:Hemoglobin, Sickle / Q000737:chemistry* / Q000235:genetics; D006453:Hemoglobinopathies / Q000097:blood* / Q000235:genetics; D006455:Hemoglobins, Abnormal / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D007525:Isoelectric Focusing; D007700:Kinetics; D046911:Macromolecular Substances; D008297:Male; D008855:Microscopy, Electron, Scanning; D010108:Oxyhemoglobins / Q000737:chemistry; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011108:Polymers
D006451:Hemoglobin, Sickle; D006455:Hemoglobins, Abnormal; D046911:Macromolecular Substances; D010108:Oxyhemoglobins; D011108:Polymers; D006444:Hemoglobin C; C031679:hemoglobin G Philadelphia