Base substitution in an intervening sequence of a β ⁺-thalassemic human globin gene

β globin gene fragments from a patient with homozygous β ⁺-thalassemia have been cloned and subjected to restriction endonuclease, nucleotide sequence, and in vitro transcription analyses. Restriction endonuclease mapping of the cloned gene fragments revealed no deletions or other rearrangements, and transcription of the thalassemic gene appeared to be normal in vitro. However, nucleotide sequence analysis of the β ⁺-thalassemic gene fragments permitted identification of a single base change in the body of the small intervening sequence. This nucleotide change creates a sequence much like that of the 3' splice site of the small intervening sequence. The presence of a potential anomalous splicing site as a result of this base change suggests a mechanism for defective posttranscriptional processing of β globin mRNA precursor molecules in β ⁺-thalassemia.