Hb Aghia Sophia [alpha 62(E11)Val -> 0 (alpha 1)], an "in-frame" deletion causing alpha-thalassemia

In this report we describe a case of Hb H disease due to the interaction of the - -((MED I)) deletion with a new alpha(+)-thalassemia determinant. The molecular analysis of the proband's genomic DNA was carried out by polymer ase chain reaction amplification and sequencing of both alpha genes of the alpha(+)-thalassemia chromosome and revealed a deletion of codon 62 of the alpha 1 gene. This DNA triplet codes for a valine residue at the E11 alpha helix, which is located in the interior of the heme pocket. Substitutions o f valine E11 with other amino acid residues in the alpha as well as beta po lypeptide chains lead, in the heterozygous carrier, either to Hb M disease or to congenital non-spherocytic hemolytic anemia. We assume that the delet ion of valine at alpha 62(E11) disrupts the conformation of the alpha chain to such an extent that the mutated subunit is rapidly removed by proteolys is. The final result is an alpha-thalassemia phenotype rather than an unsta ble hemoglobin syndrome. This conclusion is supported by the apparent absen ce of an abnormal alpha chain in the peripheral blood of the patient.