Localisation ofcisRegulatory Elements at the β-Globin Locus: Analysis of Hybrid Haplotype Chromosomes

Ofori-Acquah, Solomon F.; Lalloz, M. R. A.; Layton, D. M.

doi:10.1006/bbrc.1998.9901

Cited by 20 publications

(14 citation statements)

References 41 publications

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“…The propositus' maternal thalassemia allele has been previously described as haplotype 19A [28] and in the 5Ј LCR HS2 has Senegal polymorphic characteristics (hence the Senegal-like/ Benin-like thalassemia haplotype). Both haplotypes had been previously associated with high HbF expression and with increased G ␥ expression, however, later reports have not confirmed such an association [35,36]. In this family, both the Cameroon-like/Benin-like and the Senegal-like/ Benin-like thalassemia haplotypes segregate with elevated levels of HbF, but only the Senegal-like/Beninlike haplotype was associated with increased G ␥ expression.…”

Section: Discussioncontrasting

confidence: 50%

Non‐anemic homozygous β^o thalassemia in an African‐American family: Association of high fetal hemoglobin levels with β thalassemia alleles

et al. 2001

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We have studied a four-generation (23 subjects) African-American family with ␤ o thalassemia and high fetal hemoglobin (HbF) levels. The ␤ o thalassemia in this family is due to the splicing site mutation, ␤ IVS2+1G→A, that leads to aberrant mRNA processing and the absence of ␤ globin. Two members of this family are homozygous for ␤ o thalassemia and are non-anemic. All family members who are heterozygous for the ␤ IVS2+1G→A mutation have elevated HbF, with the exception of two individuals who also have severe ␣-globin chain deficiency. We excluded linkage with the hereditary persistence of fetal hemoglobin loci on chromosomes 6 and X. We also excluded the presence of all previously described determinants in the ␤ globin gene cluster associated with elevated HbF production. One thalassemia allele is in the Cameroon-like (HS2)/Benin-like ␤ globin gene cluster haplotype, and the other is in the Senegal-like (HS2)/Benin-like ␤ globin gene cluster haplotype. We speculate that in the homozygotes, those erythroid cells that express low to absent levels of ␥ globin are selectively destroyed. In contrast, in the heterozygotes, the presence of the normal ␤ globin allele would ameliorate the globin chain imbalance and thus allow survival of erythroid cells that express the abnormal transcript, leading to a typical

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Section: Discussioncontrasting

confidence: 50%

Non‐anemic homozygous β^o thalassemia in an African‐American family: Association of high fetal hemoglobin levels with β thalassemia alleles

et al. 2001

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“…While polymorphisms in various putative regulatory elements were present in sickle cell anemia patients with different HbF levels, they were always linked to a haplotype [11,[31][32][33][34][35]. Sharing identical ␤-globin gene cluster haplotypes, as do most of our patients, does not exclude heterogeneity in functionally important polymorphisms in this gene cluster that may regulate ␥-globin gene expression [36][37][38][39][40][41]. Studies of "hybrid" haplotype ␤ S chromosomes from unselected sickle cell disease patients showed that the HS-II short tandem repeat (TA) x N10-12(TA) y differed from that typically associated with a cognate haplotype.…”

Section: Discussionmentioning

confidence: 68%

“…Studies of "hybrid" haplotype ␤ S chromosomes from unselected sickle cell disease patients showed that the HS-II short tandem repeat (TA) x N10-12(TA) y differed from that typically associated with a cognate haplotype. Each "hybrid" chromosome had a breakpoint 5Ј to the 0.5-kb pre-G ␥ gene element, suggesting that variability in HbF level associated with polymorphisms of the HS-II enhancer depended on 3Ј cis-acting elements in tight linkage disequilibrium with HS-II [36]. While hypersensitive sites and their core sequences are conserved among mammalian genomes, percentage identity plots of the human and mouse ␤-globin gene clusters uncovered sequences outside the cores of hypersensitive sites that were as conserved as the cores themselves and contributed to the ability of DNA fragments containing the LCR to establish and/or maintain an open chromatin domain after their stable integration into genomic DNA [40,42,43].…”

Section: Discussionmentioning

confidence: 99%

Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease

et al. 2003

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“…Individuals with the sickle cell trait whose ,Bs-chromosome carries the Senegal and Arab-I ndia haplotype arc not anemic and have normal HbF levels. Alternatively, this mutation may represent a polymorphic marker linked to other mutations, for example in HS-2, that are critical for regulating {'C -globin gene expression [20]. It appears that in hematopoietic stress, elements in cis to the ,B-globin gene cluster arc associated with differences in the levels of HbF.…”

Section: Ix-globin Gene Cluster Haplotypes-effects On Hbf Levels Hemmentioning

confidence: 99%

Role of Epistatic (Modifier) Genes in the Modulation of the Phenotypic Diversity of Sickle Cell Anemia

Nagel

Steinberg

2001

Pediatric Pathology & Molecular Medicine

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Sickle hemoglobin is the product of one mutated gene, but the disease phenotype is the product of many genes. Polymorphism among the genes responsible for the pleotropic effects can be epistatic (or modifier) genes contributing to interindividual variation that characterizes sickle cell anemia patients. Modulation in the hemoglobin F levels is associated with the beta-globin gene cluster haplotypes and to gender and chromosomal sites different from chromosome 11 influencing the severity of the disease. Coexistence of alpha thalassemia with sickle cell disease produces hematologic and clinical consequences that are beneficial in some complications but deleterious in others. There is little if any modulation of the phenotype of sickle cell anemia by coexistence of G6PD deficiency. Mutations that favor blood coagulation or thrombosis may influence the phenotype of the disease. Improved understanding of the influence of genes involved in modulating the complex pathophysiology of sickle cell disease may allow prediction of the phenotype of sickle cell patients and aid in management decisions.

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Localisation ofcisRegulatory Elements at the β-Globin Locus: Analysis of Hybrid Haplotype Chromosomes

Cited by 20 publications

References 41 publications

Non‐anemic homozygous β^o thalassemia in an African‐American family: Association of high fetal hemoglobin levels with β thalassemia alleles

Non‐anemic homozygous β^o thalassemia in an African‐American family: Association of high fetal hemoglobin levels with β thalassemia alleles

Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease

Role of Epistatic (Modifier) Genes in the Modulation of the Phenotypic Diversity of Sickle Cell Anemia

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Localisation ofcisRegulatory Elements at the β-Globin Locus: Analysis of Hybrid Haplotype Chromosomes

Cited by 20 publications

References 41 publications

Non‐anemic homozygous βo thalassemia in an African‐American family: Association of high fetal hemoglobin levels with β thalassemia alleles

Non‐anemic homozygous βo thalassemia in an African‐American family: Association of high fetal hemoglobin levels with β thalassemia alleles

Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease

Role of Epistatic (Modifier) Genes in the Modulation of the Phenotypic Diversity of Sickle Cell Anemia

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Product

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Non‐anemic homozygous β^o thalassemia in an African‐American family: Association of high fetal hemoglobin levels with β thalassemia alleles

Non‐anemic homozygous β^o thalassemia in an African‐American family: Association of high fetal hemoglobin levels with β thalassemia alleles