HbS-Oman Heterozygote: A New Dominant Sickle Syndrome

Abstract

Hemoglobin (Hb) S-Oman has two mutations in the β-chains. In addition to the classic βS mutation (β6 Glu → Val), it contains a second mutation in the same chain (β121 Glu → Lys) identical to that of HbOARAB. 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 −/ thalassemia and those with about 14% of HbS-Oman and concomitant −/− 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 CSAT 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 CSAT’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 HbOARAB, which has the same second substitution as S-Oman, has a moderately severe hemolytic anemia; when HbOARAB 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 Km 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.

The erythrocyte effects of haemoglobin OARAB

“…Based on the recent work on HbS‐Oman (α 2 β 2 6Val‐121Lys ), which produces a sickle syndrome in the heterozygous state (dominant sickle cell disease) not fully explained by the increase in polymerization tendencies, we proposed the hypothesis that the mutation found in HbO ARAB (α 2 β 2 121Lys ) induces increased red cell density leading to additional pathogenic mechanisms ( Nagel et al , 1998 ).…”

“…Second, the recent description of the clinical syndrome induced by the heterozygous state of Hb S‐Oman is of interest ( Nagel et al , 1998 ). This variant, in addition to the classic β S mutation (β6 Glu → Val), contained a second mutation in the same chain (β121 Glu → Lys) identical to that of HbO ARAB .…”

“…We have postulated ( Nagel et al , 1998 ) that the pathogenic mechanisms mediated by HbS‐Oman, in addition to the facilitation of Hb polymerization, include a direct or indirect charge‐dependent interaction between S‐Oman and the red cell membrane, resulting in changes of the intracellular Hb concentration or increased cell density, by altering transport mechanisms and increasing red cell destruction. Activation of K:Cl cotransport by haemoglobin variants has been proposed ( Fabry & Nagel, 1983), but verification has been hampered by a lack of suitable homozygous patients.…”

Sickle Cell Disease in Oman and HbS Oman: A Brief Review

“…The first is the classic Bs mutation (B6 Glu→val) and the second is in position 121 (B121 Glu→lys). 17,18 Previous reports explained that carriers of this disease in Oman present in 2 different clinical syndromes:…”

“…19 In the literature only 6 carriers have been described so far. [17][18][19] Recently, we observed quite a number of carriers in our OPD presenting as severe forms. Also, we have identified for the first time in Oman compound heterozygotes HbS-Oman that resulted in a very severe clinical manifestations presenting as transfusion dependent thalassemia major with hypersplenism early in life that was not controlled, solely, by hypertransfusion and needed both splenectomy at the age of one year and bone marrow transplantation in the second year of life.…”