A single nucleotide deletion in codon 123 of the beta-globin gene causes an inclusion body beta-thalassaemia trait: a novel elongated globin chain beta Makabe.

The beta-globin gene from a Japanese individual with an inclusion body beta-thalassaemia trait has been characterized by gene cloning and DNA sequencing. An adenine deletion was detected at the first position of codon 123 (ACCCC) of one allele whereas the other allele had a normal sequence. Heterozygosity for this mutation in the patient was confirmed by Southern blots of the genomic DNA digested with HphI, the recognition site of which is eliminated by this deletion. This one base deletion results in the shift of a reading frame in such a manner that the normal termination codon is out of phase. This frameshift mutation results in the synthesis of an elongated beta-globin chain with 10 extra amino acid residues and with an altered C-terminus. Analysis of labelled globin chains using CM-cellulose column chromatography failed to demonstrate any abnormal protein, thereby suggesting that the beta-globin chain variant is highly unstable and probably degrades rapidly after synthesis. This event will lead to an accumulation of free alpha-chains precipitating in the red blood cells and an inclusion body beta-thalassaemia phenotype would ensue.