Molecular Basis for α-Thalassemia Associated With the Structural Mutant Hemoglobin Suan-Dok (α2109LEU→ARG)

Hemoglobin (Hb) Suan-Dok (α109Arg) is a rare α-globin structural mutation that is linked to an α-thalassemia (α-thal) determinant. When inherited in trans to an α-thal-1 mutation (– –), it results in Hb H disease associated with low levels (9%) of the Suan-Dok Hb. The nature of the thalassemic defect associated with the αSD mutation has been investigated by structural and functional studies. Sequence analysis of the cloned Suan-Dok allele showed a missense mutation (T → G) at codon 109 in an otherwise normal α2-globin gene. When the α2SD-globin gene was introduced into mouse erythroleukemia cells, the steady state α-globin messenger RNA (mRNA) level was equivalent to the αA-globin gene control. Although in vitro translation of a synthetic α2SD-globin mRNA generated levels of α globin equivalent to α2A-globin mRNA at early time points, the ratio of αSD to αA globin decreased markedly at later time points. These data suggest that the thalassemic defect associated with the Suan-Dok mutation results from a significant instability of the αSD globin.