Laotian (dß)°-thalassemia: Molecular characterization of a novel deletion associated with increased production of fetal hemoglobin

Abstract

We have identified and molecularly characterized a novel deletion in the ß-globin gene cluster that increases fetal hemoglobin (HbF) synthesis in a 24-year-old Laotian man who is heterozygous for this mutation. The patient is asymptomatic with a mild anemia, hypochromia, and microcytosis (Ht = 39%, MCH = 22.8 pg, MCV = 71 fl), normal levels of HbA2 (3.0%) and 11.5% HbF ((G)?(A)? ratio 60 to 40), with heterocellular distribution (52% F cells). Extensive restriction endonuclease mapping defined the 5' breakpoint within the IVS II of the d-globin gene, between positions 775 to 781 very similar to the 5' breakpoint of the Sicilian dß-thalassemia. However, the 3' breakpoint was localized between two Pst I sites 4.7 kb 3' of the ß-globin gene, thus ending about 0.7 kb upstream from the 3' breakpoint of the Sicilian dß-thalassemia. This results in a 12.5 kb deletion of DNA. It is of interest that the 5' breakpoint of the deletion resides within an AT-rich region which has been proposed as a specific recognition signal for recombination events, while the 3' breakpoint lies within a cluster of L1 repetitive sequences (formerly known as Kpn I family repeats). The presence of the 3' breakpoints of several other deletions within this region of L1 repeats also suggests that such sequences might serve as hot spots for recombination and eventually lead to thalassemia deletions. The similarity of the 5' and 3' breakpoints of these dß-thalassemias underscores the putative regulatory role of the deleted and juxtaposed sequences on the expression of the ?-globin genes in adult life.