Dominant beta-thalassaemia: a highly unstable haemoglobin is caused by a novel 6 bp deletion of the beta-globin gene

beta-Thalassaemia is inherited as an autosomal recessive trail in most fami lies. Particular interest has recently been focused on the molecular pathol ogy of the rare forms with a dominant mode of inheritance. The index patien t and her mother, who are described in this report. displayed typical clini cal and haematological features of beta-thalassaemia intermedia with signif icant ineffective erythropoiesis and additional peripheral haemolysis. Mole cular analysis demonstrated a heterozygous genotype for a novel 6bp (TGGTCT ) deletion of the beta-globin gene involving codons 33-35. This deletion re sults in the removal of two valine residues from the beta-globin chain at p osition 33/34 (B15/B16) and the substitution of the tyrosine residue at pos ition 35 (C1) by an aspartic acid (beta 33-35 [B15-C1] Val Val-Tyr --> O-O- Asp). According to the index patient's place of birth, this abnormal haemog lobin has been termed Hb Dresden. The stability of the variant and the norm al beta-globin chains were similar during the incubation period of in vitro globin chain synthesis analysis. However. Hb Dresden is exquisitely unstab le and cannot be detected in the peripheral blood by haemoglobin electropho resis, high-performance liquid chromatography (HPLC) or isoelectric focusin g. This instability can be explained by the vital structural role of the th ree affected amino acids that, in normal haemoglobin. establish a total of nine intermolecular bonds (five hydrophobic and four polar) at both the alp ha(1)beta(1) (alpha(2)beta(2)) and the alpha(1)beta(2) (alpha(2)beta(1)) in terface.