Molecular characterization of a novel form of (A ) -thalassemia, deletion with a 3' breakpoint close to those of HPFH-3 and HPFH-4: insights for a common regulatory mechanism

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Abstract
We have molecularly characterized a novel (A.gamma..delta..beta.).degree.-thalassemia associated with increased synthesis of HbF in three members of a German family. The levels of HbF in the peripheral blood red cells of the heterozygotes ranged between 9.9% and 12.5% with heterocellular distribution in the red cells, as detected by immunofluorescence. The mutation resulted from a deletion starting about 1.5 to 1.9 kb from the 3'' end of the G.gamma.-gene and ending 27 .+-. 0.5 kb 3'' to the .beta.-globin gene. Thus, the total deletion is 52 .+-. 0.5 kb. Its 5'' breakpoint is similar to that of the previously described (A.gamma..delta..beta.).degree.-thalassemias, while the location of the 3'' breakpoint is plaed very close to the 3'' breakpoints of HPFH-4 and HPFH-3 deletions. The proximity of the 3'' breakpoint of the German (A.gamma..delta..beta.).degree.-thalassemias to those of HPFH-3 and HPFH-4 deletions raises the possibility that a common mechanism, such as the juxtaposition of an enhancer, might underlie the activation of the .gamma.-globin genes in these three mutants.