Abnormal RNA processing due to the exon mutation of β^E- globin gene

As is typical of all β-thalassaemias¹, the erythroid cells of individuals with the variant haemoglobin E (α₂β ₂^26Glu→Lys) exhibit a quantitative deficiency in their content of β-globin (in this case β^E-globin) and its messenger RNA^2,3. To determine the molecular basis of this phenotype, we have investigated the structure and expression of cloned β^E-globin genes. We report here that the complete nucleotide sequence of a β^E-gene revealed the expected GAG → AAG change in codon 26 but no other mutations. Expression of β^E- globin genes introduced into HeLa cells revealed two abnormalities of RNA processing: Slow excision of intervening sequence-1 (IVS-1) and alternative splicing into exon-1 at a cryptic donor sequence within which the codon 26 nucleotide substitution resides. These results demonstrate a disturbance in the expression of the β^E-gene attributable solely to the exon mutation - A novel mechanism for gene dysfunction.