Nagel R L, Daar S, Romero J R, Suzuka S M, Gravell D, Bouhassira E, Schwartz R S, Fabry M E, Krishnamoorthy R
Division of Hematology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA.
Blood. 1998 Dec 1;92(11):4375-82.
Hemoglobin (Hb) S-Oman has two mutations in the beta-chains. In addition to the classic betaS mutation (beta6 Glu --> Val), it contains a second mutation in the same chain (beta121 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 beta6 Val mutation which are enhanced by the second mutation at beta121. In addition, the syndrome is further enhanced by a hemolytic anemia induced by the mutation at beta121. 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.
血红蛋白（Hb）S-阿曼型在β链上有两个突变。除了经典的βS突变（β6位谷氨酸→缬氨酸）外，它在同一条链上还含有第二个与HbO-阿拉伯型相同的突变（β121位谷氨酸→赖氨酸）。我们研究了一个HbS-阿曼型杂合子携带者家系，该家系分为两种类型的患者：一类表达约20%的HbS-阿曼型并伴有β/β地中海贫血，另一类表达约14%的HbS-阿曼型并伴有β0/β0地中海贫血。HbS-阿曼型表达较高的患者患有中度强度的镰状细胞贫血（SS）临床综合征，而表达较低的患者没有临床综合征，与阿曼首次描述的单独病例相似。此外，表达较高的患者除了有折叠细胞和靶形细胞外，还表现出一种独特的不可逆镰状细胞形态，类似“纱线和织针”形状。HbS-阿曼型的CSAT与另一种超级镰状血红蛋白S-安的列斯型相同，其携带者异常血红蛋白的表达率为40%至50%，临床表现与HbS-阿曼型非常相似。由于表达水平差异如此之大而临床表现却如此相似，并且基于溶血产物的CSAT，我们得出结论，HbS-阿曼型产生的病理变化超出了其镰变倾向。在纯合子HbO-阿拉伯型（其具有与HbS-阿曼型相同的第二个替代突变）患有中度严重溶血性贫血这一事实中找到了这种额外发病机制的线索；当HbO-阿拉伯型与HbS结合时，它使这种双重杂合子的表型与SS一样严重。HbS-阿曼型红细胞（RBC）的特性包括网织红细胞比正常的致密得多（类似于SC和CC疾病），激活加尔多斯通道所需的Ca2+的Km降低（使该转运体对Ca2+更敏感），HbS-阿曼型与RBC膜的结合增加，通过等密度梯度存在致密细胞，存在折叠细胞，以及膜下有丰富的聚合核。其他特性包括在表达超过20% HbS-阿曼型的RBC中体积明显增加以及N-乙基马来酰亚胺刺激的K:Cl共转运增加。我们得出结论，杂合子HbS-阿曼型的病理变化是β6位缬氨酸突变的镰变特性的产物，该特性因β121位的第二个突变而增强。此外，该综合征因β121位突变诱导的溶血性贫血而进一步加重。我们推测这种病理变化是由于高度带正电荷的HbS-阿曼型（与正常血红蛋白有3个电荷差异）与RBC膜异常结合所致。
