HB ADANA OR ALPHA(2)59(E8)GLY-]ASP-BETA(2), A SEVERELY UNSTABLE ALPHA(1)-GLOBIN VARIANT, OBSERVED IN COMBINATION WITH THE -(ALPHA)20.5 KB ALPHA-THAL-1 DELETION IN 2 TURKISH PATIENTS

We have identified a severely unstable hemoglobin variant through sequ encing of amplified DNA involving the alpha(1)-globin gene; the mutati on is located in codon 59 (C (C) under bar G C (A) under bar G) and re sults in a Gly-->Asp replacement. This amino acid substitution concern s a glycine residue at an internal position in the E helix, which is i n close contact with a glycine residue of the B helix; introduction of the larger and charged aspartic acid residue greatly affects the stab ility of the molecule. This variant was present in association with a common alpha-thalassemia-1 deletion [-(alpha)20.5 kb] in two adults an d caused a severe type of Hb H disease with anemia, low levels of Hb A (2), increased zeta chain, and Hb Bart's. In vitro chain synthesis in reticulocytes showed a high specific activity of the variant alpha cha in. Only a minute quantity of Hb H was present but instead about 10% o f Hb Bart's was observed. The increased synthesis of gamma chains was likely due to specific characteristics of a chromosome with haplotype #3, which was present in both patients. The same family was studied 18 years ago [1]; the improved methodology presently available has led t o a corrected diagnosis for these patients. (C) 1993 Wiley-Liss, Inc.