Sickle cell hemoglobin fiber formation strongly inhibited by the stanleyville II mutation (α78 Asn → Lys)

Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin

“…41 Asn78α on the F-helix has been implicated in stabilizing the HbS fiber; consistently, a variant Hb, Stanleyville (Asn78α ↔ Lsy78α) inhibits polymerization by destabilizing ontacts between deoxy-HbS molecules. 93 This finding suggests a novel therapeutic approach involving the design of compounds that stereospecifically inhibit deoxy-HbS polymer formation while increasing the oxygen affinity of Hb.…”

Structural basis for the antipolymer activity of Hbζ2βs2trapped in a tense conformation

“…The principle that nonconservative amino-acid substitutions in the α-like subunit can mitigate biochemical and clinical characteristics of SCD has been firmly established by studies of recombinant and naturally occurring variant α-globins both in vitro and in vivo [18–22,29,49,50]. Our analyses suggest that three nonconservative substitutions--αHis20→ζGln, αAsn68→ζAsp, and αAsn78→ζGly--may be particularly important to the antipolymer activities of CO-Hb ζ 2 β s 2 (Table 2), a model that is consistent with naturally occurring mutations that alter the kinetics and/or thermodynamics of Hb S polymer assembly in vitro , or mitigate the severity of the SCD condition in vivo [21,22,29,45–48]. The antipolymer characteristics of CO-Hb ζ 2 β s 2 are likely to be additionally enhanced--though perhaps to a lesser extent--by conserved residues whose repositioning is predicted to weaken specific polymer-stabilizing hydrogen-bond interactions, as observed for ζPro114 (Table 2).…”

“…The antipolymer effect of the first exchange (α2His20→ζ2Gln20) is particularly informative as it reproduces the amino-acid substitution that defines α Le Lamentin , and alone may account for the anti-sickling characteristics of Hb ζ 2 β s 2 [20]. The potential antipolymer properties of ζAsp68 and ζGly78 are consistent with the activities of α-globin subunits containing naturally occurring mutations at the corresponding positions--αAsn68→Lys (neutral polar→basic; α Philadelphia ) and αAsn78→Gly (neutral polar→neutral; α Stanleyville )--that increase the solubility of deoxyHb S heterotetramers that incorporate them [21,22,29], maintain the benign phenotype of β s heterozygotes [45,46], and mitigate the severity of the sickle phenotype in β s homozygotes [45,47,48]. …”

Hemoglobin variants identified in the Uganda Sickle Surveillance Study

“…Compound heterozygosity for Hb S and Hb PNilotic has been reported in a Ugandan child, with Hb S levels of 39%, similar to other S heterozygotes. 31 Although not identified in our analysis, Hb Stanleyville II has been reported in association with Hb SS, showing 3 major bands in addition to Hb A and F: a band in the position of Hb S (ab S disease may moderate the disease phenotype by reducing Hb polymerization and increased mechanical stability 18,36 ; however, extrapolations regarding hematological or clinical significance are premature. 18,34,37 This study had several limitations, including inability to confirm all variants by DNA analysis because of sample degradation, and lack of accompanying red cell indices, clinical information, and family demographic information.…”