Two French Caucasian families with dominant thalassemia-like phenotypes due to hyper unstable hemoglobin variants:: Hb Sainte Seve [codon 118 (-T)] and codon 127 [CAG→TAG (Gln→Stop])

We report two French Caucasian families suffering from dominant thalassemia-like phenotypes due to hyper unstable hemoglobin (Hb) variants. In both cases, molecular analysis revealed a defect localized in the third exon of the beta-globin gene, resulting in dramatic changes of the Hb structure. The first one is a new variant, Hb Sainte Seve, that is associated with a frameshift mutation at codon 118 (-T). In the second family, the disease resulted from a truncated protein due to a stop mutation at codon 127 [CAG -> TAG (Gln -> Stop)]. These two observations are additional evidences of the important role played by helix H in Hb stability: its partial absence, or a large structural modification, seems to be the major reason for the hyper instability of such molecules.