Black β‐thalassemia homozygotes with specific sequence variations in the 5′ hypersensitive site‐2 of the locus control region have high levels of fetal hemoglobin

We have sequenced the 5′ hypersensitive‐2 (5′HS‐2) site of the locus control region (LCR) and the promoters of the two γ‐globin genes located on chromosome 11 of a black patient with mild β‐thalassemia (β‐thal) major due to a homozygosity for the C → T mutation at position – 88 of the β promoter and with a high Hb F level. Sequence variations in the 5′HS‐2 were the same as observed for the βs chromosome with haplotype number 3, while most of the Gγ promoter and the Aγ promoter had sequences similar to that of the βs chromosome with haplotype number 19. This atypical haplotype (number 19A) is apparently associated with an increased γ chain production which is particularly evident during periods of severe hematopoietic stress. Additional studies on relatives of the proband and on 10 unrelated black β‐thal homozygotes with either the C → T mutation at – 88 or the A → G mutation at –29, confirm the possible importance of the sequence differences in the 5′HS‐2, and also suggest that at least two additional factors, namely a C → T mutation at position –158 of the Gγ promoter and a relative deficiency in α chain synthesis play a (perhaps less important) role in the increased Hb F synthesis in these patients. © 1992 Wiley‐Liss, Inc.