Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4375-4382
HbS-Oman Heterozygote: A New Dominant Sickle Syndrome
Ronald L. Nagel,
Shahina Daar,
Jose R. Romero,
Sandra M. Suzuka,
David Gravell,
Eric Bouhassira,
Robert S. Schwartz,
Mary E. Fabry, and
Rajagopal Krishnamoorthy
From the Division of Hematology, Albert Einstein College of
Medicine/Montefiore Medical Center, Bronx, NY; the Division of
Endocrinology and Hypertension, Brigham and Women's Hospital, Harvard
Medical School, Boston, MA; Hôpital Robert Debré, Paris,
France; and the Department of Hematology, Hospital Sultan Qaboos
Medical School, Muscat, Sultanate of Oman.
Hemoglobin (Hb) S-Oman has two mutations in the 
-chains. In
addition to the classic S mutation (6 Glu 
Val), it contains a second mutation in the same chain (121 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
6 Val mutation which are enhanced by the second mutation at 121.
In addition, the syndrome is further enhanced by a hemolytic anemia
induced by the mutation at 121. 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.
