The deletion in a type of δ⁰-β⁰-thalassaemia begins in an inverted AluI repeat

Abstract

In hereditary persistence of fetal haemoglobin (HPFH) and δ⁰-β⁰-thalassaemia, increased levels of fetal haemoglobin (HbF) are found in adult individuals. HbF production is particularly noticeable in the former condition in which HbF levels of 20–40% are found in heterozygous patients, as opposed to 5–20% in δ⁰-β⁰-thalassaemia¹. In a minority of these cases, no obvious abnormalities have been found in the globin gene region by DNA mapping^2–6, indicating that small deletions or perhaps even point mutations in critical DNA sequences in the globin gene cluster may be responsible for these conditions. However, most cases of HPFH and δ⁰-β⁰-thalassaemia are associated with extensive deletions in the globin gene cluster^2–4,7–14. Genetic data¹⁵ and gene mapping investigations^2,4,10 provided some evidence for the location of a regulatory area, whose deletion results in continuing activity of γ-globin genes in adults, in a DNA region between the ^Aγ- and δ-globin genes, possibly 3–4 kilobases (kb) 5′ to the δ gene. The precise nature of these sequences is of great interest, because it might help elucidate the molecular mechanisms regulating globin gene expression during development. Recently, Jagadeeswaran et al. cloned¹⁶ the DNA encompassing the region of a gene deletion in a type of HPFH^2,10 and showed¹⁶ that the 5′ end point of the deletion lies in the middle of an AluI repetitive DNA sequence^17,18. We have now cloned the corresponding region from the DNA of a δ⁰-β⁰-thalassaemia patient⁴ and we report here that the deletion ends in a different AluI sequence, ≃700 nucleotides 3′ to the AluI repeat involved in the HPFH deletion, and in the opposite orientation.