Partial deletion of the 5' beta-globin gene region causes beta zero- thalassemia in members of an American black family

Padanilam, Babu J.; Felice, Alex E.; Huisman, T. H. J.

doi:10.1182/blood.v64.4.941.941

Cited by 56 publications

(8 citation statements)

References 21 publications

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“…the distinctive haematologic phenotype places this mutation in a subgroup of /3-thalassaemias all characterized by unusually high levels of Hb AL in the heterozygous state. Seven deletions causing /I-thalassaemia and affecting only the b gene have now been described (Gilman, 1987;Padanilam et a/. 1984: Popovich et a/.…”

Section: Discussionmentioning

confidence: 99%

“…This deletion is very similar to the 12.6 kb deletion of Dutch $-thalassaemia (Gilman, 1987) in which the 3' breakpoint lies within the same L1 repeat sequence. Although both these deletions are closer in size to a 12-1 3 kb category of deletions which includes two Gp-thalassaemias, the unusually high Hb A2 in heterozygotes for this Asian-Indian and the Dutch $-thalassaemia deletions is reminiscent of the haematologic phenotype of a distinct subgroup of fl-thalassaemia which now includes four other deletions (Padanilam et al, 1984;Popovich et al, 1986;Thein rt al, 1989, 1992: Diaz-Chico et al, 1987Waye et al, 1991). The deletions in this group, although differing widely in size, remove in common the 5' end of the p gene but leave the 6 gene intact.…”

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confidence: 92%

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Molecular characterization of a novel 10.3 kb deletion causing β‐thalassaemia with unusually high Hb A₂

et al. 1992

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A family of Asian-Indian descent has a variant form of beta-thalassaemia characterized by unusually high levels of Hb A2 in the heterozygous state. The propositus who is homozygous for the mutation has thalassaemia intermedia. Restriction endonuclease mapping suggested the presence of a 10.3 kilobase (kb) deletion removing the whole of the beta-globin gene. Subsequently, molecular analysis was performed by directly sequencing a specifically amplified region of genomic DNA. A 10329 basepair deletion was precisely defined which results in the loss of the 5' beta promoter region and the entire beta-globin gene. The deletion extends from 3011 bp 5' to the mRNA cap site to an L1 repeat element downstream of the beta-globin gene and is very similar to the 12.6 kb deletion of Dutch beta zero-thalassaemia. In common with four other mutations, both these deletions remove the 5' promoter region of the beta gene and all are associated with unusually elevated levels of Hb A2 in the heterozygous state.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 92%

Molecular characterization of a novel 10.3 kb deletion causing β‐thalassaemia with unusually high Hb A₂

et al. 1992

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“…The 5′ β promoter deletions, even if widely different in size, have in common the loss of the region from position -125 to +78 (relative to the Cap site) which includes the CACCC, CAAT, and TATA boxes. [12][13][14][15] Interestingly homozygotes for three common β promoter mutations, namely -88 C→T, -87 C→G, and -29 A→G, also show very high levels of HbF (average values: 64.5%, 32.5%, and 60.6% respectively). It is possible that when the β promoter region is involved there is a reduced interaction with transcription factors and LCR in favor of γ promoter interaction.…”

Section: Coinheritance Of Determinants Associated With Increased γ-Chmentioning

confidence: 99%

Relationship between Genotype and Phenotype: Thalassemia Intermedia^a

Galanello¹,

Cao²

1998

Annals of the New York Academy of Sciences

100

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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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“…A common feature of these deletions is the unusually high Hb A 2 level in heterozygotes (and the majority of the cases also present high Hb F level). The carriers of the Black 1,393-bp deletion described in the literature also have this unusual phenotype, presenting with high Hb A 2 and Hb F levels [13][14][15][16]. To our knowledge, there are only two reported cases of homozygosity for one of the abovementioned deletions: the Dutch 12.6 kb [17] and the Asian-Indian 10.3 kb [18].…”

Section: Resultsmentioning

confidence: 86%

Asymptomatic homozygous deletional β⁰‐thalassemia in an African individual

et al. 2002

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Homozygosity or compound heterozygosity for ␤ 0 -thalassemia mutations most commonly results in a transfusion-dependent thalassemia major phenotype. In this report, we describe a 55-year-old male, from Guinea-Bissau, that had been asymptomatic and never transfused until being admitted to hospital with anemia, fever, splenomegaly, and asthenia. Following hospital admission, HIV-2 and Mycobacterium tuberculosis infections were diagnosed, and biochemical and molecular studies revealed homozygosity for ␤ 0 -thalassemia. At the molecular level, this is the first description of homozygosity for the ␤ 0 -Black 1,393-bp deletion. In this case, the complete absence of ␤-globin gene expression seems to be compensated by an unusually high fetal globin gene expression (Hb F 96%). ␤-Globin haplotyping results were compatible with the propositus being homozygous for the Black 2 haplotype and for the absence of the XmnI polymorphism at −158 of G ␥-globin gene (−/−). Co-inheritance of genetic factors usually associated with high Hb F levels was not detected. Otherwise, the propositus is a heterozygote for the ␣-globin gene 3.7-kb deletion that is a beneficial modulating factor but not sufficient to explain this extremely mild phenotype. This unusual genotype/phenotype association is discussed in terms of the mechanisms underlying hemoglobin switching during development. Am. J. Hematol. 70:232-236, 2002.

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Partial deletion of the 5' beta-globin gene region causes beta zero- thalassemia in members of an American black family

Cited by 56 publications

References 21 publications

Molecular characterization of a novel 10.3 kb deletion causing β‐thalassaemia with unusually high Hb A₂

Molecular characterization of a novel 10.3 kb deletion causing β‐thalassaemia with unusually high Hb A₂

Relationship between Genotype and Phenotype: Thalassemia Intermedia^a

Asymptomatic homozygous deletional β⁰‐thalassemia in an African individual

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Partial deletion of the 5' beta-globin gene region causes beta zero- thalassemia in members of an American black family

Cited by 56 publications

References 21 publications

Molecular characterization of a novel 10.3 kb deletion causing β‐thalassaemia with unusually high Hb A2

Molecular characterization of a novel 10.3 kb deletion causing β‐thalassaemia with unusually high Hb A2

Relationship between Genotype and Phenotype: Thalassemia Intermediaa

Asymptomatic homozygous deletional β0‐thalassemia in an African individual

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Molecular characterization of a novel 10.3 kb deletion causing β‐thalassaemia with unusually high Hb A₂

Molecular characterization of a novel 10.3 kb deletion causing β‐thalassaemia with unusually high Hb A₂

Relationship between Genotype and Phenotype: Thalassemia Intermedia^a

Asymptomatic homozygous deletional β⁰‐thalassemia in an African individual