Hemoglobinopathies and their effect on parasite growth
Taylor SM, Cerami C, Fairhurst RM. Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis. PLoS Pathog. 2013;9(5):e1003327.PMID: 23696730
Hemoglobinopathy Epidemiology Genotype Molecular Pathology Clinical Phenotype   Parasite Invasion Parasite Development
a+-thal trait Global Loss of one a-globin gene (aa/a-)   Asymptomatic; normal RBC size, quantity, and peripheral blood smear Normal Norma/lreduced
a0-thal trait Global Loss of two a-globin genes (aa/-) Mild anemia Normal/reduced Normal/reduced
Hemoglobin H (HbH) disease Global Loss of three a-globin genes (a-/--) Accumulation of unpaired b-chains that form HbH and precipitate in RBCs Chronic hemolytic anemia with hepatic, splenic, skeletal, and metabolic sequelae; transfusion support required in 2nd to 3rd decade of life Reduced Reduced
Hydrops fetalis/Hb Barts Global Loss of all four a-globin genes (--/--) Accumulation of unpaired g-chains in utero, forming Hb Bart�s, which is unable to release oxygen Incompatible with extra-uterine life
Minor trait/heterozygosity Global Reduced expression of one b-globin gene   Typically asymptomatic; normal hematocrit, low mean corpuscular volume hematocrit, low mean corpuscular Normal Normal/reduced
Major Global Reduced expression of both b-globin genes Accumulation of unpaired a-chains, leading to oxidant damage to RBCs and erythroid precursors Profound anemia leading to transfusion dependence, complicated by iron overload
Hemoglobin S Central, East, and West Africa; Arabian peninsula; South Asia Glu→Val at position 6 of b-globin Aggregation of deoxygenated HbS into polymers, leading to RBC deformation, hemolysis, and microcirculatory obstruction Sickle-cell disease with frequent pain crises, transfusions, and acute chest syndrome when inherited as HbSS; asymptomatic when inherited as HbAS HbSS Increased HbSA normal Reduced Normal/reduced
Hemoglobin C West Africa, centered on western Burkina Faso and northern Ghana Glu→Lys at position 6 of b-globin Formation of hexagonal HbC crystals Mild hemolysis and anemia when inherited as HbCC; asymptomatic when inherited as HbAC HbCC Normal HbAC normal Reduced Normal
Hemoglobin E Southeast Asia, centered on border of Thailand, Laos, and Cambodia Glu→Lys at position 26 of b-globin Mildly reduced expression of b-globin due to insertion of splice site and resulting mRNA degradation Mild anemia, microcytosis, and hypochromia HbEE reduced HbAE normal Normal/reduced Normal/reduced
Hemoglobin F >50% of hemoglobin at birth, largely absent by 6 months of age Normal Tetramer consisting of two a-chains and two g-chains Greater oxygen affinity within RBCs than adult hemoglobin A due to attenuated interactions with 2,3-bisphosphoglycerate Increased/normal Reduced
b-thalassemia/HbE Global co-inheritance of β-thalassemia and the structural variant HbE, a G→A substitution in codon #26 of the β-globin gene globin chain imbalance, ineffective erythropoiesis, apoptosis, oxidative damage, and shortened red cell survival Marked clinical variability, ranging from a mild and asymptomatic anaemia to a life-threatening disorder requiring transfusions from infancy Normal/reduced Reduced
The human genome normally contains four copies of a-globin genes (in paired copies on chromosome 16: genotype aa aa) and two copies of b-globin genes (on chromosome 11). Normal adult hemoglobin (HbAA) is a tetramer of two a-globin and two b-globin proteins.
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