Novel 112 kb (epsilonGgammaAgamma) deltabeta-thalassaemia deletion in a Dutch family.

An adult autochthonous Dutch patient who had exhibited severe perinatal anaemia, with partial recovery a few months after birth, was studied for the presence of beta-thalassaemia. Southern blotting showed that the patient was heterozygous for a novel deletion in the beta-globin gene cluster, leaving the beta-gene intact. Inverse polymerase chain reaction was used to determine the breakpoint sequence. The deletion removed 112 kb starting upstream of the HOR5'b6 gene to the second intron of the Agamma-globin gene, including the locus control region. The breakpoint fragment identified a 13-bp orphan sequence not present at either side of the breakpoint.

Hb Groene Hart: a new Pro-->Ser amino acid substitution at position 119 of the alpha1-globin chain is associated with a mild alpha-thalassemia phenotype.

Alpha-Thalassemia (thal) is generally considered to be an expression defect caused mostly by deletions silencing one or more alpha-globin genes. Although nondeletional alpha-thalassemia is considered rare, in our laboratory we frequently observe alpha-thal phenotypes induced by point mutations. We report a new point mutation generating an abnormal hemoglobin (Hb) associated with a mild alpha-thal phenotype in two members of a Moroccan family, who presented with mild but persistent microcytic hypochromic parameters and a balanced beta/alpha 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 alpha0-thal deletion defects.