HbS-Oman Heterozygote: A New Dominant Sickle Syndrome

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4375-4382 ◽  
Author(s):  
Ronald L. Nagel ◽  
Shahina Daar ◽  
Jose R. Romero ◽  
Sandra M. Suzuka ◽  
David Gravell ◽  
...  

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.

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4375-4382
Author(s):  
Ronald L. Nagel ◽  
Shahina Daar ◽  
Jose R. Romero ◽  
Sandra M. Suzuka ◽  
David Gravell ◽  
...  

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.


Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 929-929
Author(s):  
Taiju Utsugisawa ◽  
Takuya Iwasaki ◽  
Takako Aoki ◽  
Yoshio Okamoto ◽  
Takahiro Kawakami ◽  
...  

Abstract Introduction: Dehydrated hereditary stomatocytosis (DHSt) or hereditary xerocytosis (HX) is a form of congenital hemolytic anemia characterized by red blood cell (RBC) dehydration. Heterozygous mutations in PIEZO1, a mechanically-activated ion channel, cause DHSt. Recently, KCNN4, which encodes the Gardos channel, has been found to be the second pathogenic gene for DHSt. DHSt is characterized by an alteration in the RBC morphology in target cells, stomatocytes, and/or echinocytes, and RBC deformability assessments by ektacytometry as well as RBC ion flux measurements are currently the standard laboratory tests for DHSt, but their use in laboratories is limited. The flow cytometric osmotic fragility (FCM-OF) test is a useful diagnostic test for hereditary spherocytosis (HS) and also for hereditary elliptocytosis (HE). In this study, we showed that the FCM-OF test could also successfully diagnose DHSt. Subjects: A total of 46 cases of RBC membrane disorders were examined, and tentative diagnoses were made based on the RBC morphology, acid glycerol lysis time, and eosin 5'-maleimide binding tests, resulting in HS (n=31), HE (n=6), and DHSt (n=9). Methods: The number of RBCs in isotonic and hypotonic buffers were measured by flow cytometry. The degree of osmotic fragility was expressed as the "percentage residual RBCs (%RRC)". We confirmed the DHSt diagnosis by the massively paralleled sequencing using our custom panels targeting 68 hemolytic anemia-related genes with the next-generation sequencer. Results: Both HS and HE patients showed a decrease in %RRC; HS (18.0±8.9%, p<0.001) and HE (41.8±15.7%, p<0.001) compared to normal control (66.7±1.5%). DHSt patients showed a significant increase (112.6±34.5%, p<0.001) in FCM-OF. Additionally, next-generation sequencing revealed consistent causative gene mutations for DHSt; PIEZO1 (p.R2488Q and p.E2496ELE) or KCNN4 (p.P204R, p.A279T and p.R352H). Discussion: We examined 77 patients with congenital hemolytic anemia recently, and 59 cases were confirmed by diagnostic tests (76.6%). The results were as follows: 48 cases of RBC membrane abnormality (62.3%), 6 cases of RBC enzymopathy (7.8%), and 5 cases of hemoglobinopathy (6.5%). Of the cases of RBC membrane disorders, 31 cases of HS, 9 cases of DHSt, and 8 cases of HE were identified. These observations suggest that DHSt is the second-most common RBC membranopathy in Japan, and that the FCM-OF test and targeted sequencing efficiently discriminate DHSt from other RBC membrane disorders. Disclosures No relevant conflicts of interest to declare.


PEDIATRICS ◽  
1955 ◽  
Vol 15 (2) ◽  
pp. 185-190
Author(s):  
James L. Morgan ◽  
Richard M. Bowles ◽  
Jerome S. Harris

Two families showing abnormal hemoglobin types are described. One case represents the fifth reported instance homozygous C disease. The clinical picture is discussed, and the importance of electrophoresis in making a definitive diagnosis is stressed.


Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2374-2378
Author(s):  
T Sugihara ◽  
RP Hebbel

An abnormal susceptibility of the sickle red blood cell (RBC) membrane to deformation could compromise its permeability barrier function and contribute to the exuberant cation leakiness occurring during the sickling phenomenon. We examined this hypothesis by subjecting RBCs at ambient oxygen tension to elliptical deformation, applying shear stress in a viscous medium under physiologic conditions. Compared with normal and high-reticulocyte control RBCs, sickle RBCs manifest an exaggerated K leak response to deformation. This leak is fully reversible, is both Cl and Ca independent, and at pHe 7.4 is fully balanced so that Kefflux equals Nainflux. This abnormal susceptibility is also evident in that the K leak in response to deformation occurs at an applied shear stress of only 141 dyne/cm2 for sickle RBCs, as compared to 204 dyne/cm2 for normal RBCs. Fresh sickle RBC membranes contain elevated amounts of lipid hydroperoxide, the presence of which is believed to provide the biochemical basis for enhanced deformation susceptibility. When examined at pHe 6.8, oxygenated sickle RBCs acquire an additional, unbalanced (Kefflux > Nainflux) component to the K leak increment specifically ascribable to deformation. Studies with inhibitors suggest that this additional component is not caused by a known leak pathway (eg, either K:Cl cotransport or the Gardos channel). This abnormal susceptibility of the sickle membrane to development of cation leakiness during deformation probably contributes to the exuberant cation leak taking place during RBC sickling.


2012 ◽  
pp. n/a-n/a ◽  
Author(s):  
Emmeline Tan ◽  
Dorothee Bienzle ◽  
Patricia Shewen ◽  
Stephen Kruth ◽  
Darren Wood

Blood ◽  
1974 ◽  
Vol 43 (2) ◽  
pp. 261-269 ◽  
Author(s):  
J. G. Adams ◽  
W. P. Winter ◽  
K. Tausk ◽  
P. Heller

Abstract A mild hemolytic anemia in a 43-yr-old black woman was attributed to the presence of an abnormal hemoglobin (Hb Rush) which migrated cathodically to Hb A at pH 8.0. Its structural abnormality was found to be in the β-chain, β101 (G3) glu → gln. Another electrophoretic band at pH 8.0 proved to be a hybrid tetramer (αA2βAβRush). Hb Rush is heat unstable. A likely explanation of the instability is the presence of an uncovered positive charge in the central cavity where normally glutamic acid in position 101 neutralizes arginine in position 104 contributing to the net neutrality in this region. This neutrality is disturbed by the substitution of glutamic acid by glutamine in Hb Rush.


2018 ◽  
Vol 4 (4) ◽  
pp. 36 ◽  
Author(s):  
Nura El-Haj ◽  
Carolyn Hoppe

Sickle cell disease (SCD) encompasses a group of inherited red cell disorders characterized by an abnormal hemoglobin, Hb S. The most common forms of SCD in the United States and Canada are identified through universal newborn screening (NBS) programs. Now carried out in all fifty U.S. states and 8 Canadian provinces, NBS for SCD represents one of the major public health advances in North America. The current status of NBS programs for hemoglobinopathies and the screening techniques employed in many regions worldwide reflect in large part the U.S. and Canadian experiences. Although the structure, screening algorithms and laboratory procedures, as well as reporting and follow up, vary between NBS programs, the overall workflow is similar. The current review summarized the historical background, current approaches, and methods used to screen newborns for SCD in the United States and Canada.


Blood ◽  
1958 ◽  
Vol 13 (10) ◽  
pp. 950-958 ◽  
Author(s):  
ROBERT D. LANGE ◽  
JOSEPH H. AKEROYD

Abstract 1. A case report and special studies of a 14-year-old girl with a congenital hemolytic anemia are reported. 2. Fourteen per cent of her erythrocytes contained unusual inclusion bodies. 3. In addition, the child has been known to pass dark urine since the age of 2½ years. The pigment probably belongs to the bilifuscin and mesobilifuscin group. 4. It is believed that the syndrome is probably caused by an inborn error in erythrocytic metabolism. 5. It has been proposed that the syndrome be named "congenital hemolytic anemia with abnormal pigment metabolism and red cell inclusion bodies."


Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2822-2825 ◽  
Author(s):  
Jeffrey J. Swensen ◽  
Archana M. Agarwal ◽  
Jose M. Esquilin ◽  
Sabina Swierczek ◽  
Ajay Perumbeti ◽  
...  

Abstract Sickle cell disease (SCD) is a classic example of a disorder with recessive Mendelian inheritance, in which each parent contributes one mutant allele to an affected offspring. However, there are exceptions to that rule. We describe here the first reported case of conversion of inherited sickle cell trait to SCD by uniparental disomy (UPD) resulting in mosaicism for SS and AS erythrocytes. A 14-year-old boy presented with splenomegaly and hemolysis. Although his father has sickle cell trait, his mother has no abnormal hemoglobin (Hb). DNA sequencing, performed to rule out Hb S/β-thalassemia, detected homozygous Hb SS. Further studies revealed mosaic UPD of the β-globin locus, more SS erythroid progenitors than AS, but a reverse ratio of erythrocytes resulting from the survival advantage of AS erythrocytes. This report exemplifies non-Mendelian genetics wherein a patient who inherited sickle cell trait has mild SCD resulting from postzygotic mitotic recombination leading to UPD.


Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 49
Author(s):  
Ralfs Buks ◽  
Tracy Dagher ◽  
Maria Rotordam ◽  
David Monedero Alonso ◽  
Sylvie Cochet ◽  
...  

Over 95% of Polycythemia Vera (PV) patients carry the V617F mutation in the tyrosine kinase Janus kinase 2 (JAK2), resulting in uncontrolled erythroid proliferation and a high risk of thrombosis. Using mass spectrometry, we analyzed the RBC membrane proteome and showed elevated levels of multiple Ca2+ binding proteins as well as endoplasmic-reticulum-residing proteins in PV RBC membranes compared with RBC membranes from healthy individuals. In this study, we investigated the impact of JAK2V617F on (1) calcium homeostasis and RBC ion channel activity and (2) protein expression and sorting during terminal erythroid differentiation. Our data from automated patch-clamp show modified calcium homeostasis in PV RBCs and cell lines expressing JAK2V617F, with a functional impact on the activity of the Gárdos channel that could contribute to cellular dehydration. We show that JAK2V617F could play a role in organelle retention during the enucleation step of erythroid differentiation, resulting in modified whole cell proteome in reticulocytes and RBCs in PV patients. Given the central role that calcium plays in the regulation of signaling pathways, our study opens new perspectives to exploring the relationship between JAK2V617F, calcium homeostasis, and cellular abnormalities in myeloproliferative neoplasms, including cellular interactions in the bloodstream in relation to thrombotic events.


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