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Characterization of a Novel Post-translational Oxidative Modification in the Distal Pocket of a Fetal Hemoglobin (γ-V68M→D) Associated with the Blue Baby Syndrome

Thursday, October 11, 2012 — Poster Session IV

2:00 p.m. – 4:00 p.m.

Natcher Conference Center, Building 45




  • M.B. Strader
  • W.A. Hicks
  • J.S. Olson
  • M.J. Weiss
  • T.L. Mollan
  • A. Alayash


Hemoglobin gene mutations are known to cause diverse hematological disorders. We are currently studying a human fetal hemoglobin (HbF) variant (in the gamma-2 subunit) caused by a missense mutation in the gamma globin gene (HBG2). This mutation results in a valine to methionine substitution at position 68 (V68M). Recently, V68M HbF was characterized in a patient exhibiting neonatal cyanosis and anemia. Kinetic data from HbF V68M indicate that the larger side chain of this methionine in the oxygen binding pocket sterically impairs oxygen uptake and binding. Methionine side chain proximity, to the reactive heme, also increases autooxidation which leads to the accumulation of ferric (Fe3+) methemoglobin, which cannot bind oxygen. Liquid chromatography tandem mass spectrometric (LC-MS/MS) analysis identified the presence of V68D from the patient. Using a proteomic approach we were able to elucidate how this conversion takes place in both patient blood and in a recombinant version of this Hb. Our data definitively links the formation of aspartic acid to an event involving autooxidation and oxidative side reactions in the presence of oxygen. This presentation provides insight into how the proximity of this residue to the reactive heme pocket results in conditions that lead to cyanosis and anemia.

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