The -158 site 5' to the G gamma gene and G gamma expression

Abstract

To test the hypothesis advanced by Gilman and Huisman that the -158 site 5′ to the G gamma gene determines the G gamma expression after the first 4 months of life, we have examined DNA from sickle cell anemia (SS) patients from Africa and beta-thalassemic homozygotes from Algeria. We find that the Xmnl site is strongly linked to the Senegal haplotype among SS patients, to haplotype IX (most probably identical to the Senegal haplotype), and to haplotype III among the Algerian thalassemics. Thalassemics with haplotypes I/I and V/V have no Xmnl site and low G gamma expression. In contrast, beta-thalassemia- associated haplotype II (also characterized by high G gamma expression) fails to exhibit the Xmnl site. We conclude that, although highly correlated, the -158 C----T substitution does not perfectly predict the presence of high G gamma expression. These findings also exclude the possibility that the Xmnl site is solely involved in the determination of high G gamma expression and suggest that either several different site substitutions in the area 5′ to the gamma gene might have the same effect or that, alternatively, the Xmnl site and its surrounding area is not involved in G gamma expression and may be only in linkage disequilibrium with a controlling sequence elsewhere.

Genetic factors involved in human Gγ and Aγ globin gene expression

“…On normal chromosomes 11, the alleles detected in the three families studied are: one allele associated with haplotype IX-Xmn+ and leading to high Gy values, one allele also associated with haplotype IX-XmnI + but leading to intermediary Gy values, and one allele associated with haplotype I-Xmn I and leading to low Gy values. Our assumption that normal chromosomes with haplotype IX and the Xmn I site are carrying alleles which determine relatively high Gy values fits well with the conclusions based on hemoglobinopathies study (2,3,7,8,9).…”

“…In b-thalassemia and sickle cell anemia patients, the y globin HbF composition has been shown to be dependent on the fi globin gene cluster haplotype (2)(3)(4)(5)(6)(7) and increased Gy to Ay ratios have been found frequently associated with a C +T substitution, at position -158 5' to the Gy globin gene, detectable by DNA digestion with the enzyme XmnI (8,9). These findings strongly sug-gest that the relative expression of the Gy and Ay globin genes is controlled by a genetic factor closely linked to the fi globin gene cluster.…”

β‐Globin gene cluster polymorphisms are strongly associated with severity of HbE/β0‐thalassemia

“…HbF expression is regulated by interactions between cis-acting sequences within the b-globin gene-like cluster and trans-acting factors (transcription factors and chromatin remodeling complex), as well as genetic factors modulating erythroid cell differentiation (20,21). One common mutation, C/T substitution at 2158 upstream to the Gg globin gene and detectable by the restriction enzyme XmnI, has consistently been associated with HbF levels (22)(23)(24)(25). Previous studies of considerably smaller groups of patients with HbE/b 0 -thalassemia and thalassemia intermedia have shown association of haplotypes comprising restriction fragment length polymorphisms in the b-globin region (XmnI site, HincII site in the e-globin gene, two HindIII sites in the Gg and Ag-globin genes, two HincII sites in and 3# to the cb-globin gene) with severity of anemia and HbF level (24,25).…”

Modifier genes in Mendelian disorders: the example of hemoglobin disorders

“…This prediction was supported by identification of the XmnI polymorphism (rs7482144) in the proximal promoter of HBG2 ( G ␥ -globin). 45,49,50 The T allele at rs7482144 is associated with increased HbF levels, and is frequent in individuals of Northern European (HapMap CEU T allele frequency: 28%) and west African (HapMap YRI T allele frequency: 5%) ancestry. The XmnI-rs7482144 polymorphism explains 2-10% of the variation in HbF levels, depending on the frequency of the T allele in the different populations considered.…”