De novo deletion within the telomeric region flanking the human α globin locus as a cause of α thalassaemia

Abstract

We have identified and characterized a Scottish individual with α thalassaemia, resulting from a de novo 48 kilobase (kb) deletion from the telomeric flanking region of the α globin cluster which occurred as a result of recombination between two misaligned repetitive elements that normally lie ∼83 kb and 131 kb from the 16p telomere. The deletion removes two previously described putative regulatory elements (HS-40 and HS-33) but leaves two other elements (HS-10 and HS-8) intact. Analysis of this deletion, together with eight other published deletions of the telomeric region, showed that they all severely downregulated α globin expression. Together they defined a 20.4-kb region of the human α cluster, which contains all of the positive cis-acting elements required to regulate α globin expression. Comparative analysis of this region with the corresponding segment of the mouse α globin cluster demonstrated conserved non-coding sequences corresponding to the putative regulatory elements HS-40 and HS-33. Although the role of HS-40 as an enhancer of α globin expression is fully established, these observations suggest that the role of HS-33 and other sequences in this region should be more fully investigated in the context of the natural human and mouse α globin loci.