Gene deletion as the cause of α thalassaemia: Genetic lesion in homozygous α thalassaemia (hydrops fetalis)

Taylor, John M.; Dozy, Andrée M.; Kan, Yuet Wai; Varmus, Harold; Lie‐Injo, Luan Eng; Ganesan, J.; Todd, D.

doi:10.1038/251392a0

Cited by 213 publications

(49 citation statements)

References 16 publications

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“…Implications for the a-thalassemia syndromes Recent studies (4,(23)(24)(25) indicate that a-thalassemia may be caused by at least partial deletion of the a-chain structural genes. The varying degrees of severity in the a-thalassemia syndromes are believed to reflect the number of a-chain genes deleted.…”

Section: Methodsmentioning

confidence: 99%

Trimodality in the proportion of hemoglobin G Philadelphia in heterozygotes: evidence for heterogeneity in the number of human alpha chain loci.

Baine¹,

Rucknagel²,

Dublin³

et al. 1976

Proc. Natl. Acad. Sci. U.S.A.

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Section: Methodsmentioning

confidence: 99%

Trimodality in the proportion of hemoglobin G Philadelphia in heterozygotes: evidence for heterogeneity in the number of human alpha chain loci.

Baine¹,

Rucknagel²,

Dublin³

et al. 1976

Proc. Natl. Acad. Sci. U.S.A.

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“…In a-thalassemia, production of a-globin chains is impaired, resulting in free b-globin polypeptides, which form an unstable hemoglobin molecule (Ingram and Stretton 1959;Ottolenghi et al 1974;Taylor et al 1974). In b-thalassemia, production of b-globin chains is defective, resulting in free unstable a-globin chains that are toxic to erythroid precursors (Fessas 1963;Fessas et al 1965).…”

Section: Hemoglobinopathiesmentioning

confidence: 99%

Pluripotent Stem Cells in Research and Treatment of Hemoglobinopathies

Arora

Daley

2012

Cold Spring Harbor Perspectives in Medicine

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“…Using an excess of DNA over cDNA, it has been demonstrated that the usual form of ao-thalassaemia from South-East Asia is caused by a gene deletion [2,3] and that the ratio of the numbers of a-globin genes found in hetero-…”

mentioning

confidence: 99%

“…With the development of very radioactive gene probes, and in particular complementary DNA prepared from globin mRNA as template with viral RNA-dependent DNA polymerase (reverse transcriptase), it has proven possible to analyse the human genome directly for the presence and number of specific globin genes [2][3][4]. Using an excess of DNA over cDNA, it has been demonstrated that the usual form of ao-thalassaemia from South-East Asia is caused by a gene deletion [2,3] and that the ratio of the numbers of a-globin genes found in hetero-zygotes and homozygotes demonstrates the presence of two or a multiple of two a-globin genes per haploid genome [4,18].…”

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Demonstration of Two alpha-Globin Genes per Human Haploid Genome for Normals and Hb J Mexico

et al. 1977

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Complementary DNA (cDNA) was prepared with viral RNA-dependent DNA polymerase using human globin messenger RNA (mRNA) as template. By selective hybridization to globin mRNA from p-thalassaemics a probe which was > 85% complementary to a-globin mRNA was purified.This was hybridized in cDNA excess to human genomic DNA, and the rate and extent of hybridization confirmed that there are two genes for a-globin per haploid genome. Cellular DNA was also prepared from peripheral blood from cases expressing the a-globin chain mutant Hb J Mexico to varying extents. This DNA was identical in hybridization behaviour to normal DNA demonstrating that the imbalanced mutant chain synthesis seen physiologically is not due to a gene deletion.From genetic and molecular data for a-thalassaemia and a-globin chain structural mutants, it has been proposed that there are two a-globin genes per human haploid genome. The four types of a-thalassaemia (a-tha12, a-thall, haemoglobin H disease and Hb Bart's hydrops foetalis) are thought to correspond to deletions of one, two, three and four a-globin genes per diploid genome respectively, as shown by genetic linkage [l] and by direct molecular hybridisation of a-globin-specific cDNA to excess DNA [2-41. In the case of a Hungarian family affected by two aglobin chain structural mutations, the presence of both mutant chains and also normal a-globin chains in a single individual demonstrates the presence of at least two a-globin genes per haploid genome [5].However, no data has yet excluded the presence of multiples of two a-globin genes per haploid genome [4]. Also, certain data on other structural mutants has been interpreted as indicating only a single a-globin gene per haploid genome. Haemoglobin Tongariki homozygotes and heterozygotes show an inheritance and gene expression pattern which is more easily explained by a single a-globin gene, although familial data is incomplete [6]. The expression of a-globin chain variants is often greater than 25% in heterozygotes.The varying expression of the structural mutants Hb G Philadelphia and Hb J Mexico have been used to argue for a heterogeneous distribution of one and two a-globin structural genes per haploid genome in these populations [7][8][9][10][11][12]221. For Hb J Mexico three defined classes of expression of the mutant chain, at 30 %, 40 % and 55 %, have been found [7,1 I]. Family studies show that individuals expressing 55 % Hb J Mexico inherit this variant from both parents (where both can be studied) and transmit the abnormal gene to every descendant. They thus can be termed homozygous (although normal a-globin chains are also expressed, presumably from a second, unaffected agene locus). The full genetic analysis has recently been published elsewhere [ l l ] .With the development of very radioactive gene probes, and in particular complementary DNA prepared from globin mRNA as template with viral RNA-dependent DNA polymerase (reverse transcriptase), it has proven possible to analyse the human genome directly for the presence and number o...

show abstract

Gene deletion as the cause of α thalassaemia: Genetic lesion in homozygous α thalassaemia (hydrops fetalis)

Cited by 213 publications

References 16 publications

Trimodality in the proportion of hemoglobin G Philadelphia in heterozygotes: evidence for heterogeneity in the number of human alpha chain loci.

Trimodality in the proportion of hemoglobin G Philadelphia in heterozygotes: evidence for heterogeneity in the number of human alpha chain loci.

Pluripotent Stem Cells in Research and Treatment of Hemoglobinopathies

Demonstration of Two alpha-Globin Genes per Human Haploid Genome for Normals and Hb J Mexico

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