Hb Cibeles [α2 CD25(B6) (Gly → Asp)]: a novel alpha chain variant causing alpha-thalassemia

Thalassemias are the most frequent monogenic disorders around the world and are a serious health problem in areas with a high incidence. Thalassemias are particularly frequent in Mediterranean countries, the Middle East, Africa, the Indian subcontinent, and in the Southeast Asia. Of these, alpha-thalassemia is inherited as an autosomal recessive disorder. alpha-thalassemias are due to a deficiency or absence of hemoglobin (Hb) alpha-chain synthesis and are characterized by microcytic and hypochromic cells anemia and a clinical phenotype varying from nearly asymptomatic to a lethal hemolytic anemia. Compound heterozygotes and some homozygotes have a moderate to severe form of alpha-thalassemia called HbH disease. Hb Bart's hydrops fetalis is a lethal form in which no alpha-globin chain is synthesized. In this study we show a new structural variant of alpha-chain, Hb Cibeles [alpha 25(B6) Gly -> Asp], in heterozygous state, which was undetectable by electrophoretic or chromatographic methods. Hb Cibeles is thus a hyper-unstable hemoglobinopathy. In this new globin chain variant, an apolar amino acid is replaced by a negatively charged amino acid. This change may be responsible for the molecular hyper-instability similar to the mutation in the adjacent residues.