DNA sequence variation associated with elevated fetal G gamma globin production

Gilman, J. G.; Huisman, T. H. J.

doi:10.1182/blood.v66.4.783.783

Cited by 344 publications

(124 citation statements)

References 24 publications

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“…The "y level in the Hb F was low for all four patients as is expected for 8-thal chromosomes without an Xmn I site, i.e. a C at position -158 to the Cap site of the "y gene (Gilman & Huisman, 1985;Diaz-Chico eta/, 1988b).…”

Section: Discussionsupporting

confidence: 65%

Severe Hb S‐β°‐thalassaemia with a T → C substitution in the donor splice site of the first intron of the β‐globin gene

et al. 1989

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Through direct sequencing and dot-blot analyses with synthetic oligonucleotide probes of amplified DNA, a new nucleotide substitution was discovered in a Black teenager with severe Hb S-beta zero-thalassaemia. The substitution involved a T----C replacement at the second position of the donor splice site of the first intervening sequence of the beta-globin gene. The clinical and haematological observations made in Black subjects with Hb S-beta zero-thalassaemia, with different types of thalassaemia, suggest severe disease resembling sickle cell anaemia. Only an occasional patient had a milder clinical course, perhaps because of a greatly increased production of fetal haemoglobin.

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Section: Discussionsupporting

confidence: 65%

Severe Hb S‐β°‐thalassaemia with a T → C substitution in the donor splice site of the first intron of the β‐globin gene

et al. 1989

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“…The most common is -158 C→T Gγ promoter substitution, which is in linkage disequilibrium with frameshift cd 6 (-A), frameshift cd 8 (-AA), and IVS2-1 G→A β-thalassemia. 16 This mutation leads to enhanced γ chain production, mainly Gγ chains, under conditions of erythropoietic stress, partially compensating for absent β chain synthesis in homozygotes for the previous reported β-thalassemia mutations, with consequent amelioration of globin chain imbalance and of the clinical phenotype. The -158 C→T Gγ promoter substitution has been found occasionally in subjects with the mild β + IVS1-6 T→C and with the severe β 0 39 C→T mutation associated with haplotype IV and IX respectively 17 (Galanello et al, unpublished observations).…”

Section: Annals New York Academy Of Sciencesmentioning

confidence: 89%

Relationship between Genotype and Phenotype: Thalassemia Intermedia^a

Galanello¹,

Cao²

1998

Annals of the New York Academy of Sciences

101

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Thalassemia intermedia encompasses a number of clinical conditions ranging in severity from beta-thalassemia carrier state to transfusion-dependent thalassemia major. The molecular bases of thalassemia intermedia, only partially defined, are very heterogeneous, but in general any factor able to reduce the globin-chain imbalance results in a milder form of thalassemia. These factors are the presence of a silent or mild beta-thalassemia allele, associated with a high residual beta-globin production, and the coinheritance of alpha-thalassemia or of genetic determinants that increase the gamma-chain production. Less frequent mechanisms are double heterozygosity for beta-thalassemia and triplicated alpha genes, and the presence of a hyperunstable hemoglobin variant. However, for a consistent number of beta zero-thalassemia homozygotes with a thalassemia intermedia phenotype the modifying factor has not been defined yet. In contrast, there are simple beta-thalassemia carriers who, for unknown reasons, have an unusually severe clinical phenotype.

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“…Seven common polymorphic restriction enzyme sites in the p globin gene cluster of each DNA sample, Hind II-E, Hind IIGGy, Hind III-*y, Hind II-$P, Hind 11-3'$/3, Avu II-/?, and Bum HI$ were studied and the &haplotypes determined (Antonarakis et al, 1982). In addition each DNA sample was digested with Xmn I and hybridized to a y-globin gene probe to determine the Xmn I site polymorphism 5' to the Gy gene (Gilman & Huisman. 1985;Thein et ul, 1987).…”

Section: Methodsmentioning

confidence: 99%

The molecular basis of thalassaemia major and thalassaemia intermedia in Asian Indians: application to prenatal diagnosis

et al. 1988

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A study of the molecular pathology of beta thalassaemia in the Asian Indian immigrant population in the U.K. included 37 patients with thalassaemia major and 14 with thalassaemia intermedia. Using a combination of oligonucleotide probe hybridization and restriction endonuclease analysis the mutations in 100/102 (98%) of the beta thalassaemia genes were characterized. Nine different types were found, of which six are associated with beta zero, one with severe beta+ and two with mild beta+ thalassaemia. Comparison of the beta-globin gene cluster haplotypes, alpha globin genotypes and beta gene mutations of the thalassaemia major group with the thalassaemia intermedia group suggests that the co-inheritance of a high Hb F determinant associated with the - + - + + 5' beta haplotype and the inheritance of a mild beta-thalassaemia mutation are the major ameliorating factors of disease severity in Asian Indians. In comparison with other population groups. beta thalassaemia in Asian Indians is not associated with one or two predominant mutations. Despite this, prenatal diagnosis by direct detection is possible in the majority of families by restriction analysis and a limited number of oligonucleotide probes since the majority of severely affected individuals are homozygous for a single mutation. The characterization of these mutations should be useful for the planning of prenatal diagnosis programmes for beta thalassaemia in other Asian Indian communities.

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DNA sequence variation associated with elevated fetal G gamma globin production

Cited by 344 publications

References 24 publications

Severe Hb S‐β°‐thalassaemia with a T → C substitution in the donor splice site of the first intron of the β‐globin gene

Severe Hb S‐β°‐thalassaemia with a T → C substitution in the donor splice site of the first intron of the β‐globin gene

Relationship between Genotype and Phenotype: Thalassemia Intermedia^a

The molecular basis of thalassaemia major and thalassaemia intermedia in Asian Indians: application to prenatal diagnosis

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DNA sequence variation associated with elevated fetal G gamma globin production

Cited by 344 publications

References 24 publications

Severe Hb S‐β°‐thalassaemia with a T → C substitution in the donor splice site of the first intron of the β‐globin gene

Severe Hb S‐β°‐thalassaemia with a T → C substitution in the donor splice site of the first intron of the β‐globin gene

Relationship between Genotype and Phenotype: Thalassemia Intermediaa

The molecular basis of thalassaemia major and thalassaemia intermedia in Asian Indians: application to prenatal diagnosis

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Product

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Relationship between Genotype and Phenotype: Thalassemia Intermedia^a