Molecular cloning and sequence analysis of a nondeletion form of Sicilian β° hereditary persistence of fetal hemoglobinemia (HPFH) (mutation in IVS2 nt1 position) homozygous for haplotype III revealed the presence of four sequence variations: C → T at -158 5' to (G)γ, T → C at +2285, C → A at +2476, and A → G at +2676, all 3' to (A)γ. The latter three variations in the putative (A)γ enhancer are identical to those observed in the case of Seattle HPFH. However, a severe β°-thalassemia case from Algeria (mutation in IVS1 nt1 position), also homozygous for haplotype III, revealed the same nucleotide variations, albeit an inefficient HbF production. We conclude that the variations in the (A)γ enhancer element do not play a role in the regulation of HbF production. To assess both the linkage of these sites with the β-cluster haplotype and the extent of the polymorphism, we examined several black and Mediterranean chromosomes, by PCR amplification followed by both EspI digestion and oligonucleotide hybridization. Our data indicate that these sequence variations in the enhancer element are absent in Mediterranean haplotypes I, V, and VII but are consistently associated with Mediterranean haplotypes II, III, and IX, as well as with the black β°-associated haplotype. The common feature of all the latter haplotypes is the presence of a polymorphic PvuII site between (A)γ and ψβ, which is thus the linkage disequilibrium with the variations in the (A)γ enhancer. To verify such linkage we examined samples of haplotype VI from Sicily, some with PvuII (+) site (VI(s)) and others with PvuII (-); we found the PvuII (+) haplotype VI(s) linked to C, A, and G in the (A)γ enhancer. We conclude that the PvuII site separates haplotypes in two groups linked to different variations in the 3' enhancer and should be useful in understanding the phylogeny of β-globin haplotypes.
|Original language||English (US)|
|Number of pages||6|
|Journal||American Journal of Human Genetics|
|Publication status||Published - Jan 1 1989|
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