Hemoglobin Brockton [.beta.138 (H16) Ala .fwdarw. Pro]: an unstable variant near the C-terminus of the .beta.-subunits with normal oxygen-binding properties

Abstract

Hemoglobin Brockton [beta 138 (H16) Ala----Pro] is an unstable variant associated with a mild anemia. It has the same electrophoretic mobility as and cannot be resolved from Hb A. Oxygen affinity measurements of blood and hemolysate do not indicate biphasic oxygen saturation, showing that the functional properties of the variant are very similar to those of Hb A. This implies that the introduction of proline into the H-helix at position 138 does not disrupt the critical inter- and intrasubunit hydrogen bonds and salt bridges at the beta carboxyl-terminal dipeptide, since these polar interactions are essential for the normal oxygen-binding properties of hemoglobin. X-ray crystallographic data are consistent with these findings and show that the consequences of the beta 138 Ala----Pro substitution are almost entirely confined to the immediate vicinity of the mutation site. Instability probably results from the inability of a buried hydrogen bond to form between Pro 138 beta and Val 134 beta.

Five Variants of the β-Globin Gene without Clinical or Hematological Effects: Hb Maryland [β47(CD6)Asp→His], Hb Kent [β37(C3)Trp→Cys], Hb Visayan [β136(H14)Gly→Cys], Hb Cutlerville [β138(H16)Ala→Val] and Hb Hornchurch [β43(CD2)Glu→Lys]

“…Hb Brockton [β138(H16)Ala→Pro] is the only other variant reported at this position. It is an unstable Hb variant presenting with hemolytic anemia and reticulocytosis (16). The lack of separation of Hb Cutlerville on most media is likely explained by a neutral charge substitution of the involved amino acids.…”

Hemoglobin Variants: Biochemical Properties and Clinical Correlates

“…For example, in Hb Brockton (b138 [H16] Ala . Pro) the substituted proline disrupts intermolecular hydrogen bonding between b138Ala and b134Val in helix H (Russu and Ho 1986;Moo-Penn et al 1988). This produces an unstable variant with a propensity to precipitate and aggregate, thereby damaging erythrocytes and predisposing to hemolysis.…”

“…Hb Brockton does not show altered O 2 binding affinity or electrophoretic mobility shifts. This variant was identified by HPLC analysis of patient globin chains and its altered X-ray crystallography diffraction pattern shows local disruption of helix H (Moo-Penn et al 1988). …”

Congenital Methemoglobinemia and Unstable Hemoglobin Variant in a Child With Cyanosis

“…The characteristic element of type 2 is a persistent, progressive neurologic deterioration. This disease is associated with mental retardation, microcephaly, opisthotonos, athetoid movements, and generalized hypertonia [9,10]. Type II constitutes approximately 10% of all cases and typically leads to death within the first few years of life as the severity of disease is an immediate result of the global deficiency in NADH-cytochrome b5 reductase.…”