Köln's unstable hemoglobin: case report and literature review

Pscheidt, Sandra; Pereima, Ivana M.L.; Roberge, Márcia B.; Rotolo, M.; Genovez, Guilherme; Zunino, João Nilson

doi:10.1590/s1676-24442003000100007

Cited by 4 publications

(5 citation statements)

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“…Due to the loss of the hydrogen bond with the 26th residue, the side chain of His117 β flips and its NE2 atom now interacts with another water molecule (not shown in the figure). Previous studies on hemoglobin instabilities suggest that HbE can be unstable when subjected to an increase in temperature ( , ). Our structural studies show that, although there is no direct hydrogen bond between helices B and G near the mutation site of HbE (Figure b), the intersubunit contacts remain the same as those of HbA, presumably due to the presence of the water network that partially connects helices B and G. Among these water molecules, only W2 and W3 are buried, while the other members of this network are on the surface.…”

Section: Resultsmentioning

confidence: 99%

“…Thermal denaturation experiments performed on blood from E/β-thalassemics in the temperature range of 39-41 °C showed the instability of HbE, a finding that was also observed in homozygous HbE (14). Pscheidt et al (15) also showed the instability of HbE by performing a heat test at 50-60 °C, and they suggested that, in particular, any change that reduces the contacts between the subunits that compose the hemoglobin would generate its instability.…”

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confidence: 93%

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Crystal Structures of HbA₂ and HbE and Modeling of Hemoglobin δ₄: Interpretation of the Thermal Stability and the Antisickling Effect of HbA₂ and Identification of the Ferrocyanide Binding Site in Hb

et al. 2004

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Hemoglobin A(2) (alpha(2)delta(2)) is an important hemoglobin variant which is a minor component (2-3%) in the circulating red blood cells, and its elevated concentration in beta-thalassemia is a useful clinical diagnostic. In beta-thalassemia major, where there is beta-chain production failure, HbA(2) acts as the predominant oxygen deliverer. HbA(2) has two more important features. (1) It is more resistant to thermal denaturation than HbA, and (2) it inhibits the polymerization of deoxy sickle hemoglobin (HbS). Hemoglobin E (E26K(beta)), formed as a result of the splice site mutation on exon 1 of the beta-globin gene, is another important hemoglobin variant which is known to be unstable at high temperatures. Both heterozygous HbE (HbAE) and homozygous HbE (HbEE) are benign disorders, but when HbE combines with beta-thalassemia, it causes E/beta-thalassemia which has severe clinical consequences. In this paper, we present the crystal structures of HbA(2) and HbE at 2.20 and 1.74 A resolution, respectively, in their R2 states, which have been used here to provide the probable explanations of the thermal stability and instability of HbA(2) and HbE. Using the coordinates of R2 state HbA(2), we modeled the structure of T state HbA(2) which allowed us to address the structural basis of the antisickling property of HbA(2). Using the coordinates of the delta-chain of HbA(2) (R2 state), we also modeled the structure of hemoglobin homotetramer delta(4) that occurs in the case of rare HbH disease. From the differences in intersubunit contacts among beta(4), gamma(4), and delta(4), we formed a hypothesis regarding the possible tetramerization pathway of delta(4). The crystal structure of a ferrocyanide-bound HbA(2) at 1.88 A resolution is also presented here, which throws light on the location and the mode of binding of ferrocyanide anion with hemoglobin, predominantly using the residues involved in DPG binding. The pH dependence of ferrocyanide binding with hemoglobin has also been investigated.

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Section: Resultsmentioning

confidence: 99%

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confidence: 93%

Crystal Structures of HbA₂ and HbE and Modeling of Hemoglobin δ₄: Interpretation of the Thermal Stability and the Antisickling Effect of HbA₂ and Identification of the Ferrocyanide Binding Site in Hb

et al. 2004

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“…Unstable hemoglobins are a group of genetic variants of hemoglobins in which the mutation of amino acids into alpha and beta globins affect the structure of the molecule, making it unstable. Some hemoglobins are discreetly unstable and are not associated with clinical symptoms, while other unstable hemoglobins precipitate with great intensity, causing hemolytic anemia, excretion of "free heme" such as dipyrroles, making the patient's urine dark 4 . Kӧln haemoglobin was first described by Pribilla et al in 1965, where they found a "new" haemoglobin in haemoglobin electrophoresis, forming a small band between HbA and HbA2, constituting around 5% of total haemoglobin.…”

Section: Discussionmentioning

confidence: 99%

Targeted Next Generation Sequencing (NGS) to Diagnose Hereditary Hemolytic Anemias

Bharadwaj

Raman

Thangadorai

et al. 2020

IJHOSCR

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Hereditary hemolytic anemias present a unique diagnostic challenge due to their wide phenotypic and genotypic spectrum. Accurate diagnosis is essential to ensure appropriate treatment. We report two cases, which presented as hemolytic anemias, but initial workup was inconclusive and they were finally diagnosed with the help of Next Generation Sequencing (Dehydrated Hereditary Stomatocytosis and Kӧln Hemoglobinopathy). The introduction of gene sequencing to aid diagnosis of these disorders is a revolutionary step forward and should be incorporated earlier in the workup of such patients.

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“…1 Patients with Hgb Köln typically have reticulocytosis, splenomegaly, bilirubin, jaundice, and prolonged dark urine excretion in addition to moderate hemolytic anemia. 2 Prolonged thrombocytopenia or priapism were also reported in certain cases. 3,4 Hemoglobin Köln reports are more common among several regions of the Orient, and throughout Europe.…”

Section: Introductionmentioning

confidence: 99%

Common Clinical Manifestations and a Rare Diagnosis: A Case Report of Hemoglobin Köln in Saudi

Alzahrani¹,

Malibari²,

Abdalla³

et al. 2023

AJHMN

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Background: Hemoglobin Köln is the most widely diagnosed among unstable hemoglobin. Patients with hemoglobin Köln often have moderate hemolytic anemia, reticulocytosis, splenomegaly, and high levels of lactate dehydrogenase and bilirubin in the blood. Hemoglobin Köln happened as a result of the substitution of an amino acid methionine for the usual valine at position 98 of the beta chain. Up to the time, there were no previous reports in Arabian Peninsula, hence, the patient involved in this study is considered to be the first reported case. Case: A 13 years old Saudi male, product of consanguineous marriage, known to have chronic hemolytic anemia and jaundice since birth. Previously labeled as query Gilbert syndrome and treated with folic acid supplements by primary health care. However, due to the several emergency room admissions caused by severe left upper quadrant abdominal pain in association with dark urine, gallstones and hepatosplenomegaly, the patient was referred to pediatric hematology. Subsequent investigations identified that patient's vague and common complaints was a result of hemoglobin Köln disease. Those investigations showed mild macrocytic anemia, polychromasia, and bite cells in blood smear, while in hemoglobin electrophoresis, a small peak in zone (E) was observed. Hemoglobin Köln was confirmed by whole exome sequencing (WES) test that reported the presence of amino acid exchange (Val99Met). Recommendations: Careful examination is necessary for the differential diagnosis of hemoglobinopathy variations, which can be challenging especially in pediatric cases. Unstable hemoglobin should be investigated in cases mimicking a β-thalassemia trait, but associated with abnormally rapid hemolysis and reticulocytosis, or in cases that cannot be explained with common causes.

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Köln's unstable hemoglobin: case report and literature review

Cited by 4 publications

References 1 publication

Crystal Structures of HbA₂ and HbE and Modeling of Hemoglobin δ₄: Interpretation of the Thermal Stability and the Antisickling Effect of HbA₂ and Identification of the Ferrocyanide Binding Site in Hb

Crystal Structures of HbA₂ and HbE and Modeling of Hemoglobin δ₄: Interpretation of the Thermal Stability and the Antisickling Effect of HbA₂ and Identification of the Ferrocyanide Binding Site in Hb

Targeted Next Generation Sequencing (NGS) to Diagnose Hereditary Hemolytic Anemias

Common Clinical Manifestations and a Rare Diagnosis: A Case Report of Hemoglobin Köln in Saudi

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Köln's unstable hemoglobin: case report and literature review

Cited by 4 publications

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Crystal Structures of HbA2 and HbE and Modeling of Hemoglobin δ4: Interpretation of the Thermal Stability and the Antisickling Effect of HbA2 and Identification of the Ferrocyanide Binding Site in Hb

Crystal Structures of HbA2 and HbE and Modeling of Hemoglobin δ4: Interpretation of the Thermal Stability and the Antisickling Effect of HbA2 and Identification of the Ferrocyanide Binding Site in Hb

Targeted Next Generation Sequencing (NGS) to Diagnose Hereditary Hemolytic Anemias

Common Clinical Manifestations and a Rare Diagnosis: A Case Report of Hemoglobin Köln in Saudi

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Product

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Crystal Structures of HbA₂ and HbE and Modeling of Hemoglobin δ₄: Interpretation of the Thermal Stability and the Antisickling Effect of HbA₂ and Identification of the Ferrocyanide Binding Site in Hb

Crystal Structures of HbA₂ and HbE and Modeling of Hemoglobin δ₄: Interpretation of the Thermal Stability and the Antisickling Effect of HbA₂ and Identification of the Ferrocyanide Binding Site in Hb