Sequence variations in the 5' hypersensitive site-2 of the locus control region of beta S chromosomes are associated with different levels of fetal globin in hemoglobin S homozygotes

Abstract

We have compared the sequence of the 5′ hypersensitive site-2 (5′-HS-2) of the locus control region (LCR) from a sickle cell anemia (SS) patient homozygous for haplotype 19 and with low levels of fetal hemoglobin (HbF), with the same sequence from an SS patient homozygous for haplotype 3 and with high levels of HbF. Several nucleotide variations were present in the 5′HS-2 of the haplotype 19 individual. One is the A----G at position -10905 that creates an Sp1 binding site GCCCC (A----G)CCCC. A second is the T----G at position -10924 in a sequence that binds both erythroid and ubiquitous factors and exhibits high homology to the long terminal repeat of the Moloney leukemia viruses and Friend murine leukemia virus. Other differences were in the two AT-rich stretches of DNA, and an A----T substitution at position - 10390. Dot-blot analyses of amplified DNA from several SS patients showed that these variations are specific for beta S chromosomes with haplotype 19. We also examined the 5′HS-2 sequence from an SS patient who is homozygous for haplotype 19, but has abnormally high levels of HbF (greater than 20%). We observed a cross-over that has placed sequences similar to the 5′HS-2 of haplotype 3 in juxtaposition to the 5′ flanking regions of haplotype 19. Thus, a beta S chromosome with haplotype 19 but having a 5′HS-2 (LCR) characteristic for haplotype 3 is associated with high gamma-chain expression. We postulate that factors produced under conditions of hematopoietic stress, together with genetic determinants on the haplotype 3-like LCR sequences, allow for high level expression of gamma-globin genes.

Beta‐globin gene cluster haplotypes as evidence of African gene flow to the northeastern coast of Venezuela

“…High frequencies of the Benin haplotype have been reported in many other countries of the Americas such as Canada, the United States, Jamaica, Guadeloupe, and Surinam (Antonarakis et al, 1984;Ke Âclard et al, 1996;O È ner et al, 1992). However, in Cuba, Brazil, and Mexico the most frequent haplotype is Bantu (Muniz et al, 1995;Pante de Souza et al 1999;Pen Äaloza et al, 1995).…”

“…The Venezuelan gene pool is the product of admixture between Native Americans, European colonizers, and Africans brought as slaves mainly between 1500 and 1810 (Aizpurua, 1988). Venezuelans with an Wainscoat et al, 1983;Antonarakis et al, 1984;Hattori et al, 1986;Nagel et al, 1991;O È ner et al, 1992;Zago et al, 1992;Costa et al, 1994;Gonc Ëalves et al, 1994;Muniz et al, 1995;Pen Äaloza et al, 1995;Ke Âclard et al, 1996;Olivero, 1996;Franca et al, 1998;Pante  de Sousa et al, 1998;Bortolini and Salzano, 1999;Arends et al, 2000. important African component occupy a vast region along the Caribbean coast, from the eastern to the western part of the country (Arends, 1971;Brito Figueroa, 1983;Arends et al, 1985Arends et al, , 1990Arends et al, , 2000Castro de Guerra, 1992;Castro de Guerra et al, 1997). The presence of high frequencies of Bantu and Benin haplotypes, and in lower frequencies the Senegal haplotype, suggest that the mutation HBB*S in the Sucre and Anzoa Âtegui states is mainly of Bantu origin.…”

Gender and haplotype effects upon hematological manifestations of adult sickle cell anemia

“…The Senegal haplotype is associated with a high proportion of Gy chains, and often, but not always, higher levels of Hb F than with other haplotypes [6,. Senegal haplotype-specific portions of hypersensitive site I1 (HS-11) of the p locus control region have been implicated in high Hb F expression [36,41]. In some studies, increases in Hb F have been accompanied by higher hemoglobin concentrations and fewer dense cells [6,18].…”

Polymorphic pattern of the (AT)x(T)y motif at −530 5′ to the β‐globin gene in over 40 patients homozygous for various β‐thalassemia mutations

“…Considerable effort has been made to identify the genetic determinants of y chain expression among patients with S S and P-thal because higher levels of Hb F ameliorate the clinical course of these diseases. The putative cis-acting determinants include the -158 (C-T) mutation in the Gy promoter [23-251, the LCR 5'HS-2 [22,26], and the negative regulatory elements in the P-globin gene promoter which suppress (3 chain synthesis [3][4][5][6]. While an X-linked factor has been identified [27,28], and it is also recognized that the co-existence of a-thal is associated with decreased Hb F levels [29], it is generally agreed that there are other, as yet, unidentified trans-acting factors.…”