HbS-Oman heterozygote: A new dominant sickle syndrome

Hemoglobin (Hb) S-Oman has two mutations in the β-chains. In addition to the classic β(S) mutation (β6 Glu → Val), it contains a second mutation in the same chain (β121 Glu → Lys) identical to that of HbO(ARAB). We have studied a pedigree of heterozygous carriers of HbS-Oman that segregates into two types of patients: those expressing about 20% HbS-Oman and concomitant - α/αα thalassemia and those with about 14% of HbS-Oman and concomitant - α/-α thalassemia. The higher expressors of S-Oman have a sickle cell anemia (SS) clinical syndrome of moderate intensity, while the lower expressors have no clinical syndrome, and are comparable to the solitary case first described in Oman. In addition, the higher expressors exhibit a unique form of irreversibly sickled cell reminiscent of a 'yarn and knitting needle' shape, in addition to folded and target cells. The C(SAT) of S-Oman is identical to that of S-Antilles, another supersickling hemoglobin, whose carriers express the abnormal hemoglobin at 40% to 50%, with a very similar clinical picture to HbS-Oman. Because the level of expression is so different and the clinical picture so similar, and based on the hemolysates C(SAT)'s, we conclude that HbS-Oman produces pathology beyond its sickling tendencies. A clue for this additional pathogenesis is found in the fact that homozygous HbO(ARAB), which has the same second substitution as S-Oman, has a moderately severe hemolytic anemia; when HbO(ARAB) is combined with HbS, it makes the phenotype of this double heterozygote as severe as SS. Properties of HbS-Oman red blood cells (RBCs) include reticulocytes that are much denser than normal (similar to those of SC and CC disease), a decrease in the K(m) for Ca²⁺ needed to activate the Gardos' channel (making this transporter more sensitive to Ca²⁺), increased association of HbS-Oman with the RBC membrane, the presence of dense cells by isopycnic gradient, the presence of folded cells, and abundant nidus of polymerization under the membrane. Other properties include a clear increase in volume and N-ethylmaleimide-stimulated K:Cl cotransport in RBCs expressing more than 20% HbS-Oman. We conclude that the pathology of heterozygous S-Oman is the product of the sickling properties of the β6 Val mutation which are enhanced by the second mutation at β121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the mutation at β121. We speculate that this pathology results from the abnormal association of the highly positively charged HbS-Oman (3 charges different from normal hemoglobin) with the RBC membrane.