Hemoglobin Yakima: I. Clinical and Biochemical Studies*

Jones, Richard T.; Osgood, Edwin E.; Brimhall, Bernadine; Koler, Robert D.

doi:10.1172/jci105674

Cited by 117 publications

(34 citation statements)

References 17 publications

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“…In recent years, studies of families with dominantly inherited erythrocytosis have established hemoglobinopathy as the main etiologic possibility (4-9). Thus far, in all the families with hemoglobinopathic erythrocytosis, an abnormal hemoglobin was readily demonstrable with electrophoretic or chromatographic techniques (4)(5)(6)(7)(8)(9). This, however, is not necessary for diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…The delineation of the structural and functional aberrations of these hemoglobins and the elucidation of the pathophysiological basis of crythrocytosis have contributed significantly to the understanding of molecular disease in man (1)(2)(3)(4). Abnormal electrophoretic or chromatograp)hic patterns are characteristic of all the described mutants (4)(5)(6)(7)(8)(9). We report a new variant associated with abnormal oxygen equilibria and erythrocytosis which was defined only after detailed structural studies on isolated globin chains.…”

Section: Introductionmentioning

confidence: 99%

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Hemoglobin Olympia (β20 Valine → Methionine): An Electrophoretically Silent Variant Associated with High Oxygen Affinity and Erythrocytosis

Stamatoyannopoulos¹,

Nute²,

Adamson³

et al. 1973

J. Clin. Invest.

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A B s T R A C T In a family with erythrocytosis, electrophoretic and chromatographic studies failed to demonstrate a hemoglobin variant. However, the oxygen dissociation curves of affected individuals were shifted to the left of normal and this shift persisted when oxygen equilibria were studied in 2,3-diphosphoglycerate-stripped hemolysates. A mutant hemoglobin was evidently present in the red blood cells of the affected persons and was responsible for the increased oxygen affinity and erythrocytosis. Specific staining of tryptic peptidle maps of P-chains from the propositus showed that peptide PT3 was positive for a sulfur-containing amino acid. Amino acid analysis yielded a composition identical to that of normal PT3, except that there were 2.6 residues of valine and 0.4 residues of methionine (normal composition: Val = 3.0, Met = 0). This suggested that the P-chains of affected individuals consisted of a mixture of two kinds of chains, 40% of which had a methionyl residue in PT3. Structural studies of isolated cyanogen bromide fragments demonstrated unequivocally that, in the abnormal P-chains, valine in position 20 is replaced by methionine. The new hemoglobin mutant is designated hemoglobin Olympia (P20 (B2) valine >methion-ine).

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hemoglobin Olympia (β20 Valine → Methionine): An Electrophoretically Silent Variant Associated with High Oxygen Affinity and Erythrocytosis

Stamatoyannopoulos¹,

Nute²,

Adamson³

et al. 1973

J. Clin. Invest.

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“…The properties of several natural Hb with mutations at Asp-99(fi) have been reported in some detail by several investigators (Jones et al, 1967;Rucknagel et al, 1967;Reed et al, 1968; natural mutant showed greater susceptibility toward tetramerdimer dissociation in both the oxygenated and the deoxygenated states. For example, whereas the dimer-tetramer dissociation constant for normal human HbA is about lo-' M in its oxygenated state and M in its deoxygenated form (Turner et al, 1981), the corresponding values for the natural mutants at Asp%(@) are increased by 3-5 orders of magnitude (Turner et al, 1981Doyle et al, 1992).…”

Section: Dissociation Of the Mutant Hbmentioning

confidence: 92%

“…These mutant Hb include Hb Kempsey (Asp "+ Asn) (Reed et al, 1968;Bunn et al, 1974), Hb Yakima (Asp + His) (Jones et al, 1967), Hb Radcliffe (Asp + Ala) (Weatherall et al, 1977). Hb Ypsilanti (Asp + Tyr) (Rucknagel et al, 1%7), Hb Hotel-Dieu (Asp "* Gly) [Blouquit et al.…”

mentioning

confidence: 99%

Properties of a recombinant human hemoglobin with aspartic acid 99 (β), an important intersubunit contact site, substituted by lysine

Yanase¹,

Cahill²,

Llano³

et al. 1994

Protein Science

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Site-directed mutagenesis of an important subunit contact site, , by a Lys residue (D99K(@)) was proven by sequencing the entire @-globin gene and the mutant tryptic peptide. Oxygen equilibrium curves of the mutant hemoglobin (Hb) (2-15 mM in heme) indicated that it had an increased oxygen affinity and a lowered but significant amount of cooperativity compared to native HbA. However, in contrast to normal HbA, oxygen binding of the recombinant mutant Hb was only marginally affected by the allosteric regulators 2,3-diphosphoglycerate or inositol hexaphosphate and was not at all responsive to chloride. The efficiency of oxygen binding by HbA in the presence of allosteric regulators was limited by the mutant Hb. At concentrations of 0.2 mM or lower in heme, the mutant D99K(@) Hb was predominantly a dimer as demonstrated by gel filtration, haptoglobin binding, fluorescence quenching, and light scattering. The purified dimeric recombinant Hb mutant exists in 2 forms that are separable on isoelectric focusing by about 0.1 pH unit, in contrast to tetrameric hemoglobin, which shows 1 band. These mutant forms, which were present in a ratio of 60:40, had the same masses for their heme and globin moieties as determined by mass spectrometry. The elution positions of the a-and @-globin subunits on HPLC were identical. Circular dichroism studies showed that one form of the mutant Hb had a negative ellipticity at 410 nm and the other had positive ellipticity at this wavelength. The findings suggest that the 2 D99K(@) recombinant mutant forms have differences in their heme-protein environments.

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“…Although this latter study did not characterize the erythrocytosis extensively, the spleen enlargement and expanded splenic erythropoiesis reported reconciles with our observations that Hbb-b2 Plt12/Plt12 mice had elevated circulating concentrations of EPO and a profound erythrocytosis with splenomegaly and excess CFU-E, consistent with tissue hypoxia causing overproduction of red blood cells driven by excess EPO-driven erythropoiesis. In humans heterozygous for mutations affecting the homologous residue in Hb β, EPO measurements have not always yielded consistent results, but high concentrations have been reported (16), suggesting a similar mechanism drives erythrocytosis in these patients. Genetic modifiers influenced the lethal phenotype in Hbb-b2 Plt12/Plt12 mice.…”

Section: Discussionmentioning

confidence: 99%

Thrombocytopenia and erythrocytosis in mice with a mutation in the gene encoding the hemoglobin β minor chain

Kauppi

Hilton²,

Metcalf

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Diverse mutations in the genes encoding hemoglobin (Hb) have been characterized in human disease. We describe here a mutation in the mouse Hbb-b2 gene, denoted Plt12 , that precisely mimics the human hemoglobin Hotel Dieu variant. The mutation results in increased affinity of Hb for oxygen and Plt12 mutant mice exhibited reduced partial pressure of O 2 in the blood, accompanied by erythrocytosis characterized by elevated erythropoietin levels and splenomegaly with excess erythropoiesis. Most homozygous Hbb-b2 Plt12/Plt12 mice succumbed to early lethality associated with emphysema, cardiac abnormalities, and liver degeneration. Survivors displayed a marked thrombocytopenia without significant deficiencies in the numbers of megakaryocytes or megakaryocyte progenitor cells. The lifespan of platelets in the circulation of Hbb-b2 Plt12/Plt12 mice was normal, and splenectomy did not correct the thrombocytopenia, suggesting that increased sequestration was unlikely to be a major contributor. These data, together with the observation that megakaryocytes in Hbb-b2 Plt12/Plt12 mice appeared smaller and deficient in cytoplasm, support a model in which hypoxia causes thrombocytopenia as a consequence of an inability of megakaryocytes, once formed, to properly mature and produce sufficient platelets. The Plt12 mouse is a model of high O 2 -affinity hemoglobinopathy and provides insights into hematopoiesis under conditions of chronic hypoxia.

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Hemoglobin Yakima: I. Clinical and Biochemical Studies*

Cited by 117 publications

References 17 publications

Hemoglobin Olympia (β20 Valine → Methionine): An Electrophoretically Silent Variant Associated with High Oxygen Affinity and Erythrocytosis

Hemoglobin Olympia (β20 Valine → Methionine): An Electrophoretically Silent Variant Associated with High Oxygen Affinity and Erythrocytosis

Properties of a recombinant human hemoglobin with aspartic acid 99 (β), an important intersubunit contact site, substituted by lysine

Thrombocytopenia and erythrocytosis in mice with a mutation in the gene encoding the hemoglobin β minor chain

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