HEMOGLOBIN OLD DOMINION BURTON-UPON-TRENT, BETA-143 (H21) HIS-]TYR, CODON-143 CAC-]TAC-A VARIANT WITH ALTERED OXYGEN-AFFINITY THAT COMPROMISES MEASUREMENT OF GLYCATED HEMOGLOBIN IN DIABETES-MELLITUS - STRUCTURE, FUNCTION, AND DNA-SEQUENCE

Objective: To determine the nature and characteristics of a unique hem oglobin variant that causes a spurious increase in glycated hemoglobin (Hb A(1c)). Material and Methods: Blood specimens from four unrelated persons with this hemoglobin variant were examined by conventional la boratory methods, including electrophoresis, high-performance ion-exch ange chromatography, and isoelectric focusing; by amino acid sequence analysis, polymerase chain reaction-based DNA sequence analysis, and e lectrospray ionization mass spectrometry, to establish the molecular s tructure; and by studies of oxygen affinity under varied conditions, t o define the functional characteristics of the hemoglobin variant. Res ults: The unique hemoglobin variant observed in these four cases is du e to the mutation CAC-->TAC, at beta-globin gene codon 143, correspond ing to beta 143 (H21) His-->Tyr. This amino acid substitution affects an important 2,3-diphosphoglycerate binding site and slightly increase s the oxygen affinity of the hemoglobin variant. Conclusion: A hithert o unrecognized hemoglobin variant, encountered in fur unrelated person s of Irish or Scots-Irish ancestry, hemoglobin Old Dominion/Burton-upo n-Trent, beta 143 (H21) His-->Tyr, has now been characterized at the m olecular, structural, and functional levels. Although it is associated with a slight increase in oxygen affinity, it is without hematologic effect, and its only clinical significance is that it coelutes with Hb A(1c) on ion-exchange chromatography and thereby causes a spurious in crease in Hb A(1c) and compromises the use of this analyte to monitor the treatment of diabetes mellitus.