Hb GROENE HART: A NEW Pro→Ser AMINO ACID SUBSTITUTION AT POSITION 119 OF THE α1-GLOBIN CHAIN IS ASSOCIATED WITH A MILD α-THALASSEMIA PHENOTYPE

Abstract

α-Thalassemia (thal) is generally considered to be an expression defect caused mostly by deletions silencing one or more α-globin genes. Although nondeletional α-thalassemia is considered rare, in our laboratory we frequently observe α-thal phenotypes induced by point mutations.

We report a new point mutation generating an abnormal hemoglobin (Hb) associated with a mild α-thal phenotype in two members of a Moroccan family, who presented with mild but persistent microcytic hypochromic parameters and a balanced β/α synthetic ratio. All attempts to separate an abnormal native or denatured fraction were unsuccessful using electrophoresis, isoelectrofocusing (IEE), ion exchange and reversed phase high performance liquid chromatography (HPLC), denaturing polyacrylamide gel electrophoresis (PAGE), and electrospray mass spectrometry (ES/MS). The anomalous protein was only predictable by DNA analysis. The mutated gene product, not separable with any of the techniques used, could be a monomer unsuitable for tetramer formation, which is proteolyzed at an early stage. Alternatively, this mutation could perhaps lead to an abnormal splicing. The CCTCT sequence generated by the mutant, not found in the translated region of the gene, but normally present at the end of the IVS-II, could induce a possible exon skipping. This mutant could generate a mild or a critical Hb H disease in combination with one of the common α⁰-thal deletion defects.