A 15-year-old boy is found to have unexplained erythrocytosis on routine laboratory analysis. Evaluation of his immediate family shows that his father and sister also have elevated red cell levels. Genetic sequencing of the β-globin gene is performed in the affected family members. The results show a single base substitution at amino acid position 82 that replaces the normal lysine residue with methionine. Further analysis shows that this amino acid replacement impairs the ionic interaction between the β-subunit and 2,3-bisphosphoglycerate. As a result of this mutation, the patient's hemoglobin will be most similar to which of the following hemoglobin types?
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This patient most likely has familial erythrocytosis due to a β-globin mutation resulting in reduced binding of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-BPG is synthesized from glycolytic intermediates and binds strongly to deoxyhemoglobin in a pocket formed between the 2 beta chains. This binding reduces the oxygen affinity of hemoglobin, allowing more oxygen to diffuse into the peripheral tissues. The hemoglobin 2,3-BPG binding pocket contains positively charged amino acids (eg, histidine and lysine) that attract the negatively charged phosphate groups in 2,3-BPG. Mutations that decrease the positive charge of the binding site decrease 2,3-BPG binding and increase hemoglobin oxygen affinity.
Fetal hemoglobin (hemoglobin F) is synthesized primarily during fetal development (~8 weeks until term) and consists of the usual 2 alpha chains with 2 gamma chains in place of beta chains. The gamma chains do not bind effectively to 2,3-BPG due to replacement of a histidine residue with serine. As a result, fetal hemoglobin has significantly higher oxygen affinity than adult hemoglobin A. This allows fetal hemoglobin to extract more oxygen from the mother's adult hemoglobin in the placenta, providing the developing fetus with an adequate supply of oxygen.
(Choice A) Hemoglobin A1c is formed by non-enzymatic glycosylation of hemoglobin A. Glycosylation can interfere with the binding of 2,3-BPG to hemoglobin by altering the physical structure of the binding pocket, which is compensated for by increased red cell 2,3-BPG levels in patients with diabetes. However, the reduced 2,3-BPG binding affinity of this patient’s mutated hemoglobin more closely resembles that of hemoglobin F.
(Choice B) Hemoglobin C results from a mutation in the β-globin chain that causes glutamate to be replaced by lysine. Hemoglobin C forms hexagonal crystals and promotes red cell dehydration, causing a mild chronic hemolytic anemia. 2,3-BPG binding and tissue oxygen delivery are not significantly altered.
(Choice D) A defect in the synthesis of alpha chains results in varying degrees of alpha thalassemia, which is characterized by the formation of β-globin and γ-globin tetramers (hemoglobin H and Barts, respectively). These abnormal tetramers have extremely high oxygen affinity (resembling myoglobin) and are ineffective at delivering oxygen to tissues.
(Choice E) Hemoglobin S is the predominant form of hemoglobin in sickle cell disease and is caused by replacement of a glutamate by valine in the β-globin chain. This results in formation of hemoglobin polymers with reduced oxygen affinity.
Educational objective:
2,3-bisphosphoglycerate (2,3-BPG) normally forms ionic bonds with the beta subunits of deoxygenated hemoglobin A, facilitating oxygen release in the peripheral tissues. Mutations that result in loss of the 2,3-BPG binding pocket's positive charge cause hemoglobin A to resemble fetal hemoglobin, which binds oxygen with a higher affinity due to its inability to interact with 2,3-BPG.