Distinct phenotypic expression associated with a new hyperunstable alpha globin variant (Hb Heraklion, alpha 1cd37(C2)Pro > 0): Comparison to other alpha-thalassemic hemoglobinopathies

Clinical phenotypes associated with abnormal globin chain biosynthesis may result in thalassemia (deficient quantity) or hemolytic anemia (abnormal he moglobins). However, the phenotypic expression of hyperunstable hemoglobin variants often includes features of thalasssemia, along with variable perip heral hemolysis, Hemoglobinopathies caused by highly unstable beta -chain v ariants have a dominant thalassemia-like phenotype, in which carriers have a clinical expression of thalassemia intermedia, but highly unstable alpha -globin variants are usually only phenotypically apparent when they interac t with other alpha -thalassemia mutations. In a child with clinical and hem atological features consistent with beta -thalassemia intermedia, DNA analy sis excluded any beta -globin gene mutations but characterized a novel dele tion cd37(C2)Pro>0 (Hb Heraklion) in the alpha1 globin gene, in trans to a common Mediterranean nondeletion alpha -thalassemia mutation (alpha (Hph)al pha). Th, deletion of proline at alpha 37(C2) is predicted to result in sev ere instability of the variant hemoglobin, which on interaction with a synt hesis-deficient alpha -thalassemia mutation causes a relatively severe dyse rythropoietic anemia, representing an alternative phenotype associated with highly unstable alpha -chain variants, Hb Heraklion is the fourth highly u nstable alpha -globin variant that we have observed in patients from Greece and Albania. Two variants involve the alpha2-globin gene: Hb Agrinio (alph a 29(B10)Leu>Pro) and Hb Adana (alpha 59(E8)Gly>Asp), and two the alpha1-ge ne: Wb Aghia Sophia (alpha 62(E11)Val>0) and (Hb Heraklion a37(C2)Pro>0), E ach has been observed on interaction with a different alpha -thalassemia mu tation and the phenotypes associated with these highly unstable alpha -vari ants are presented. (C) 2000 Academic Press.