Hemoglobin Brisbane: beta68 Leu replaced by His. A new high oxygen affinity variant

Hemoglobin Brisbane is a new hemoglobin variant which produces a mile erythrocytosis. It is not detectable by electrophoresis at pH 8.6 or by isoelectric focusing but it is mildly unstable and gives a positive result with standard stability tests. The new hemoglobin has increased oxygen affinity and reduced co-operativity with a normal Bohr effect and 2,3-DPG binding. Structural analysis shows that a histidine residue has replaced the leucine normally found at position beta 68 (E12).     

Hb-Alberta or alpha2beta2 (101(G3) Glu replaced by Gly), a new high-oxygen-affinity hemoglobin variant causing erythrocytosis.

Hb-Alberta has been found in a 51 year old Caucasian male with erythrocytosis. The substitution in this variant involves the glutamyl residue in position 101(G3) of the beta chain which is replaced by a glycyl residue. Hb-Alberta accounts for about 45% in the heterozygote, and readily forms hybrid tetramers with other hemoglobins. The oxygen affinity of Hb-Alberta is greatly increased, its Bohr effect reduced, and its subunit interaction greatly diminished.     

Hemoglobin Riyadh--alpha2beta2 (120(GH3)Lys replaced by Asn). A new variant found in association with alpha-thalassemia and iron deficiency.

On a field trip toSaudi Arabia (M.A.F.E.H.) in which the relationship between alpha-thalassemia and iron deficiency was studied, a fast moving hemoglobin variant was noted in a 30 year old Saudi Arabian woman. Analysis of the hemoglobin variant showed that the amino acid substitution was beta120 Lys replaced by Asn. This variant had not been described previously and has been named Hb Riyadh. There was also present an alpha-thalassemia and details are given of the imbalance of globin chain synthesis. It was possible to improve considerably the balance in vitro by the addition of hemin.     

Hemoglobin Baylor (alpha2beta281(EF5) leu replaced by Arg)--an unstable mutant with high oxygen affinity.

The amino acid substitution in a new hemoglobin variant, Hb Baylor (alpha2beta281 (EF5) Leu replaced by Arg), has been determined by application of column chromatography and amino acid analysis of the tryptic peptides. The hemoglobin is somewhat unstable and it has a high oxygen affinity. The propositus shows the opposing hematologic effects of these two properties--the instability being associated with increased destruction, and the high O2 affinity with increased production, of erythrocytes.     

Hemoglobin Ohio (beta 142 Ala replaced by): a new abnormal hemoglobin with high oxygen affinity and erythrocytosis

Hemoglobin Ohio [beta 142 (H20) Ala replaced by Asp] was found in three members of a white family, all of whom showed erythrocytosis. The variant hemoglobin has a high oxygen affinity, a reduced Bohr effect, and diminished cooperativity. The functional abnormalities of Hb Ohio are explained by the proximity of the substituent beta 142 residue, both to beta 143 His, which is involved in the DPG binding site of hemoglobin, and to the critical C terminal region of the beta chain, which participates in the stabilization of the deoxy (T) conformation.     

Hemoglobin Suan-Dok (alpha 2 109 (G16) Leu replaced by Arg beta 2): an unstable variant associated with alpha-thalassemia.

An abnormal hemoglobin variant was detected in a seven-year old Thai girl. The clinical and hematological pictures were indistinguishable from hemoglobin H disease. Upon cellulose acetate electrophoresis at pH 8.5 an abnormal hemoglobin variant was found together with hemoglobins A and H. The variant moved slightly behind HbF and amounted to approximately 9%. Globin chain synthesis studies of peripheral blood reticulocytes incubated with tritiated leucine revealed that the total radioactivity ratio alpha-chain + variant alpha-chain/beta-chain was 0.59, while the ratio variant alpha-chain/beta-chain was 0.12. The variant hemoglobin was somewhat unstable under heat denaturation and in the isopropanol test. Structural studies by component isolation, globin chain separation, peptide mapping and aminoacid analysis of abnormal peptides showed that the leucine residue 109 of the alpha-chain was replaced by arginine. This hemoglobin mutant has not been described before and is named Hemoglobin Suan-Dok.     

Hemoglobin Sunshine Seth - alpha 2 (94 (G1) Asp replaced by His) beta 2.

Hemoglobin Sunshine Seth in which a histidyl is substituted for an aspartyl residue at position 94 of the alpha chain was detected at birth in a Caucasian male infant during cord blood screening and is present also in the mother and a male sibling. Although the substitution is in the alpha 1 beta 2 contact, it is without obvious deleterious effect on the hematological parameters or the health of the affected individuals.     

Hemoglobin Gavello - alpha 2 beta 2 47 (CD6) Asp replaced by Gly. A new hemoglobin variant from Polesine (Italy)

During a survey for abnormal hemoglobins in Polesine (a region north of the Po river, where beta-thalassemia is very frequent) a slow moving variant was noted in a 79-yr-old woman living in Gavello, a small town in the province of Rovigo. Structural studies demonstrated a previously undescribed amino acid substitution, beta47 Asp replaced by Gly. This new variant has been named Hb Gavello.     

Hb Toyoake: beta 142 (H20) Ala replaced by Pro. A new unstable hemoglobin with high oxygen affinity

A new unstable hemoglobin with high oxygen affinity, Hb Toyoake: beta 142 (H20) Ala replaced by Pro, was found in Japanese male with a normal blood hemoglobin level, shortened red cell survival, and increased plasma erythropoietin. Hemoglobin studies showed heat and isopropanol instability, and an increased tendency to heme loss and to subunit dissociation. Electrophoresis of whole hemolysate showed inconstant abnormal bands with reduced mobilities due to progressive heme loss during the in vitro procedure. Isolated Hb Toyoake with normal heme content migrated slightly faster than HbA. Oxygen affinity of red cells was elevated with P50 of 17.0 mm Hg at pH 7.4 and 37 degrees C (normal 25.0 mm Hg). Studies on hemolysate implied that Hb Toyoake had an almost normal Bohr effect, a diminished cooperativity, and a reduced response to inositol hexaphosphate. These multiple abnormalities are associated with a substitution of Pro for beta 142 Ala, resulting in disruption of the H-helix and the adjacent C-terminal portion of beta chain, which contain residues crucial for normal oxygen binding.     

Hb Regina or alpha 2 beta 2 96(FG3)Leu----Val: a high oxygen affinity variant discovered by cation-exchange HPLC

Results are reported of studies of the hemoglobin from one member of a Canadian family with a mild erythrocytosis. This variant, which accounted for about 40% of the hemoglobin, could be separated from Hb A and Hb A2 by cation-exchange chromatography. Micro methodology allowed the characterization of a Leu----Val replacement at position beta 96(FG3). Hb Regina has an increased oxygen affinity, which adequately explains the hematological observations.     

Hemoglobin Chico [beta 66(E10)Lys----Thr]: a new variant with decreased oxygen affinity

Hemoglobin Chico was discovered in an asymptomatic 3-year-old boy when a mild anemia was detected by a routine blood count. Affected individuals in three generations are also mildly anemic. The abnormal hemoglobin amounts to about 45% of the total. It separates from Hb A by cellulose acetate electrophoresis at pH 8.5 with a mobility similar to Hb J but does not separate in citrate agar at pH 6.2. Stability in isopropanol is slightly decreased. Its structure differs from the normal by the substitution of a threonyl residue for lysyl residue at position 66(E10) of the beta chain. The P50 of the oxygen equilibrium curve of whole blood at 37 degrees C was 38 torr compared with controls of 27 +/- 2 torr. The P50 binding studies of the isolated Hb Chico revealed a unique right shift of the equilibrium curve with an oxygen binding constant (1/P50) about half of normal. The remaining allosteric properties were essentially normal. This significant decrease in oxygen affinity appears to be due to changes in the heme region which result from the substitution of the normal beta 66 lysyl by the threonyl residue.