scholarly journals An alpha-globin gene initiation codon mutation in a black family with HbH disease

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 729-732 ◽  
Author(s):  
NF Olivieri ◽  
LS Chang ◽  
AO Poon ◽  
AM Michelson ◽  
SH Orkin
Keyword(s):  
Molecular Basis ◽  
Restriction Site ◽  
Black Family ◽  
Globin Gene ◽  
Initiation Codon ◽  
Cloning And Sequencing ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Codon Mutation ◽  
Thalassemia Mutation

Abstract The molecular basis of hemoglobin H disease in a Black family of Canadian origin was investigated. Affected individuals had a combination of deletion and nondeletion alpha-thalassemia mutations on different chromosomes. Cloning and sequencing of the DNA of one member with the nondeletion form revealed a new thalassemia mutation, an A---- G substitution, in the initiation codon of the remaining alpha-globin gene of a rightward (-alpha 3.7) deletion chromosome. This mutation abolished an Ncol restriction site and therefore is detectable in genomic DNA by Southern blot analysis.

scholarly journals An alpha-globin gene initiation codon mutation in a black family with HbH disease

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 729-732
Author(s):  
NF Olivieri ◽  
LS Chang ◽  
AO Poon ◽  
AM Michelson ◽  
SH Orkin
Keyword(s):  
Molecular Basis ◽  
Restriction Site ◽  
Black Family ◽  
Globin Gene ◽  
Initiation Codon ◽  
Cloning And Sequencing ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Codon Mutation ◽  
Thalassemia Mutation

The molecular basis of hemoglobin H disease in a Black family of Canadian origin was investigated. Affected individuals had a combination of deletion and nondeletion alpha-thalassemia mutations on different chromosomes. Cloning and sequencing of the DNA of one member with the nondeletion form revealed a new thalassemia mutation, an A---- G substitution, in the initiation codon of the remaining alpha-globin gene of a rightward (-alpha 3.7) deletion chromosome. This mutation abolished an Ncol restriction site and therefore is detectable in genomic DNA by Southern blot analysis.

scholarly journals AN INITIATION CODON MUTATION IN THE α1 GLOBIN GENE OF A BLACK FAMILY WITH HbH DISEASE

1987 ◽  
Vol 21 (4) ◽  
pp. 303A-303A
Author(s):  
Nancy F Olivieri ◽  
Annette O Poon ◽  
Lebe S Chang ◽  
Alan M Michelson ◽  
Stuart H Orkin
Keyword(s):  
Black Family ◽  
Globin Gene ◽  
Initiation Codon ◽  
Codon Mutation ◽  
Hbh Disease

scholarly journals Molecular basis of hemoglobin-H disease in the Mediterranean population

Blood ◽  
1979 ◽  
Vol 54 (6) ◽  
pp. 1434-1438
Author(s):  
YW Kan ◽  
AM Dozy ◽  
G Stamatoyannopoulos ◽  
MG Hadjiminas ◽  
Z Zachariades ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Gene Deletion ◽  
Globin Gene ◽  
Mediterranean Population ◽  
Mediterranean Populations ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
The Mediterranean ◽  
Endonuclease Mapping ◽  
Hemoglobin H Disease

We investigated the molecular basis of hemoglobin-H disease by hybridization and restriction endonuclease mapping of the DNA in the Mediterranean populations. Of the 12 patients studied from Cyprus and Sardinia, 8 had the typical deletion defect with a single remaining alpha-globin gene. The nondeletion type of alpha-thalassemia was found in 3, and a “dysfunctional” gene in one. We conclude that the predominant cause of alpha-thalassemia in these populations is gene deletion.

scholarly journals Molecular basis of hemoglobin-H disease in the Mediterranean population

Blood ◽  
1979 ◽  
Vol 54 (6) ◽  
pp. 1434-1438 ◽  
Author(s):  
YW Kan ◽  
AM Dozy ◽  
G Stamatoyannopoulos ◽  
MG Hadjiminas ◽  
Z Zachariades ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Gene Deletion ◽  
Globin Gene ◽  
Mediterranean Population ◽  
Mediterranean Populations ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
The Mediterranean ◽  
Endonuclease Mapping ◽  
Hemoglobin H Disease

Abstract We investigated the molecular basis of hemoglobin-H disease by hybridization and restriction endonuclease mapping of the DNA in the Mediterranean populations. Of the 12 patients studied from Cyprus and Sardinia, 8 had the typical deletion defect with a single remaining alpha-globin gene. The nondeletion type of alpha-thalassemia was found in 3, and a “dysfunctional” gene in one. We conclude that the predominant cause of alpha-thalassemia in these populations is gene deletion.

scholarly journals Inactivation of mouse alpha-globin gene by homologous recombination: mouse model of hemoglobin H disease

Blood ◽  
1996 ◽  
Vol 88 (5) ◽  
pp. 1846-1851 ◽  
Author(s):  
J Chang ◽  
RH Lu ◽  
SM Xu ◽  
J Meneses ◽  
K Chan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mouse Model ◽  
Knockout Mice ◽  
Globin Gene ◽  
Embryonic Stem ◽  
Globin Genes ◽  
Human Homologue ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Hemoglobin H Disease

We have disrupted the 5′ locus of the duplicated adult alpha-globin genes by gene targeting in the mouse embryonic stem cells and created mice with alpha-thalassemia syndromes. The heterozygous knockout mice (.alpha/alpha alpha) are asymptomatic like the silent carriers in humans whereas the homozygous knockout mice (.alpha/.alpha) show hemolytic anemia. Mice with three dysfunctional alpha-globin genes generated by breeding the 5′ alpha-globin knockouts (.alpha/alpha alpha) and the deletion type alpha-thalassemia mice (../alpha alpha) produce severe hemoglobin H disease and they die in utero. These results indicate that the 5′ alpha-globin gene is the predominant locus in mice, and suggest that it is even more dominant than its human homologue.

scholarly journals The effect of alpha-thalassemia on the expression of the beta- thalassemia/HPFH heterozygote in a black family

Blood ◽  
1981 ◽  
Vol 57 (6) ◽  
pp. 1132-1134 ◽  
Author(s):  
E Beutler ◽  
E Turner ◽  
W Kuhl
Keyword(s):  
Black Family ◽  
Clinical Manifestations ◽  
Fetal Hemoglobin ◽  
Pedigree Analysis ◽  
Red Cells ◽  
Beta Thalassemia ◽  
Hemoglobin Gene ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Hereditary Persistence

Abstract A 2-yr-old black girl presented with a thalassemic clinical picture and was found to have nearly 100% fetal hemoglobin in her red cells. Pedigree analysis indicated that she was a heterozygote for the hereditary persistence of fetal hemoglobin gene and for a beta O- thalassemia gene. A brother, who also had nearly 100% fetal hemoglobin in his red cells, manifested, in contrast to his sister, no anemia and only minimal splenomegaly. Examination of the family's alpha-globin loci using the restriction endonuclease Eco Rl demonstrated that the brother had a single alpha-locus deletion that he had inherited from his mother. The mild clinical manifestations of this boy are consistent with the often expressed view that excess alpha chains may contribute significantly to the hematologic manifestation of beta-thalassemia.

scholarly journals The detection and use of hemoglobin mutants in the direct analysis of human globin genes

Blood ◽  
1980 ◽  
Vol 55 (6) ◽  
pp. 1060-1062 ◽  
Author(s):  
PF Little ◽  
E Whitelaw ◽  
G Annison ◽  
R Williamson ◽  
JM Kooter ◽  
...  
Keyword(s):  
Restriction Site ◽  
Globin Gene ◽  
Direct Analysis ◽  
Globin Genes ◽  
Beta Globin ◽  
Gene Sequences ◽  
Gamma Globin ◽  
Alpha Globin ◽  
Specific Restriction ◽  
Alpha Beta

Abstract Many human globin-chain mutants contain amino acid replacements that result from single base changes in the corresponding globin gene. Using recombinants, the coding sequences of each of the alpha-, beta-, Ggamma- , and Agamma-globin genes have now been determined. Those sequences of DNA that are cleaved by a number of specific restriction endonucleases have been identified and accurately positioned. Mutations at these sequences abolish the restriction site, and therefore, the pattern of DNA fragments containing hybridizing globin-gene sequences is altered compared to DNA from normal persons. This allows the identification of one of a pair of cross-hybridizing human globin-gene sequences, as is shown here for the two alpha-globin, the two gamma-globin, and the delta- and beta-globin genes.

scholarly journals The alpha-globin gene adjacent to the gene for HbQ-alpha 74 Asp replaced by His is deleted, but not that adjacent to the gene for HbG- alpha 30 Glu replaced by Gln; three-fourths of the alpha-globin genes are deleted in HbQ-alpha-thalassemia

Blood ◽  
1979 ◽  
Vol 54 (6) ◽  
pp. 1407-1416 ◽  
Author(s):  
LE Lie-Injo ◽  
AM Dozy ◽  
YW Kan ◽  
M Lopes ◽  
D Todd
Keyword(s):  
Restriction Enzyme ◽  
Bone Marrow Cells ◽  
Globin Gene ◽  
White Blood Cells ◽  
Mutant Gene ◽  
Chinese Patients ◽  
Globin Genes ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Beta 2

Abstract Two Chinese patients with HbQ-alpha 2 74 Asp replaced by His beta 2- alpha-thalassemia, one HbQ-alpha 2 74 or 75 Asp replaced by His beta 2 carrier, and one HbG-alpha 2 30 Glu replaced by Gln beta 2 carrier were studied to determine the number of alpha-globin genes in their chromosomes. DNA was isolated from white blood cells and bone marrow cells and studied by liquid hybridization and by hybridization of DNA fragments obtained by restriction enzyme endonuclease digestion (Ecr to nitrocellulose filters. The liquid hybridization analysis showed that in HbQ-alpha 2 74 Asp replaced by His beta 2-alpha-thalassemia, as in HbH disease, only one-fourth of the usual number of alpha-globin genes is present. Hybridization patterns of DNA restriction enzyme fragments showed that in HbQ-alpha 2 74 Asp replaced by His beta 2-alpha- thalassemia one chromosome has both alpha-globin genes deleted and the other chromosome, which carries the alpha-mutant gene, has one alpha- globin gene deleted. Our results show that the HbQ-alpha 74 Asp replaced by His structural gene is located adjacent to a deleted alpha- globin gene, whereas the alpha-globin gene adjacent to HbG-alpha 30 Glu replaced by Gln gene is not deleted.

scholarly journals Interaction of rare illegitimate recombination event and a poly A addition site mutation resulting in a severe form of alpha thalassemia

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3356-3362 ◽  
Author(s):  
P Fortina ◽  
T Parrella ◽  
M Sartore ◽  
E Gottardi ◽  
V Gabutti ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Sequence Analysis ◽  
Recombination Event ◽  
Globin Gene ◽  
Severe Form ◽  
Illegitimate Recombination ◽  
Chain Reaction ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Polymerase Chain

Abstract The clinical diversity of thalassemia depends on interaction of diverse genetic defects. We have characterized a severe form of alpha thalassemia caused by coinheritance of a rare alpha-globin gene deletion and a nondeletional defect in a southern Italian family. The proband, a 7-year-old girl, exhibited an abnormal hemoglobin electrophoresis pattern with hemoglobin H and hemoglobin Barts, indicating inheritance of H and hemoglobin Barts, indicating inheritance of a severe form of alpha thalassemia. Southern blot analysis of DNA showed normal as well as aberrant alpha-globin gene fragments indicating heterozygosity for a deletional form of alpha thalassemia in the proband and her mother. The coinheritance of a nondeletional form of alpha thalassemia (alpha alpha T) was suspected because of the severity of the proband's phenotype and the presence of normal alpha-globin gene fragments in the father. Selective polymerase chain reaction of the paternal alpha 1- and alpha 2-globin genes in the proband followed by DNA sequence analysis showed an AATAAA to AATGAA mutation in the polyadenylation signal sequence of the alpha 2-globin gene. Genomic DNA mapping and sequence analysis of a unique polymerase chain reaction product generated across the deletion breakpoint of the maternal allele showed a 5,201-bp deletion extending from 870 nucleotides 5′ of the alpha 2-globin gene to nucleotide +519 in the alpha 1-globin gene. This deletion is similar to that previously suggested by blotting studies in a Greek family (Pressley et al, Nucleic Acids Res 8:4889, 1980) and removes the entire alpha 2-globin gene and a portion of the 5′ end of the alpha 1-globin gene. Sequence characterization of the resultant aberrant truncated alpha 1-globin gene from the proband showed a 27 nucleotide duplication corresponding to the 3′ end of the alpha-globin gene IVS-2 region separated by the insertion of a tetranucleotide (GGTT), suggesting that this deletion is caused by an illegitimate recombination event.

Phenotypic effect of heterozygous alpha and beta 0-thalassemia interaction

Blood ◽  
1983 ◽  
Vol 62 (1) ◽  
pp. 226-229 ◽  
Author(s):  
MA Melis ◽  
M Pirastu ◽  
R Galanello ◽  
M Furbetta ◽  
T Tuveri ◽  
...  
Keyword(s):  
Globin Gene ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Phenotypic Effect ◽  
Screening Programs ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Red Blood Cell Indices ◽  
Endonuclease Mapping ◽  
Glucose 6 Phosphate Dehydrogenase

In this study, we carried out restriction endonuclease mapping in order to characterize the alpha-globin genotype of 10 Sardinian beta 0- thalassemia heterozygotes, all of whom presented with normal red blood cell indices and increased HbA2 levels. In 8 of these subjects, we found the deletion of two alpha-globin genes (-alpha/-alpha), and in the remaining two the deletion of a single alpha-globin gene (- alpha/alpha alpha). In three of these carriers with the (-alpha/-alpha) alpha-globin genotype and in one with the (-alpha/alpha alpha) genotype, we also found the glucose-6-phosphate dehydrogenase (G6PD) defect of the Mediterranean type. On the basis of these findings, we may conclude that the interaction of heterozygous beta 0-thalassemia with alpha-thalassemia, due to the deletion of either one or two alpha- globin genes, may lead to the production of red blood cells with normal indices. The association of the G6PD defect with this thalassemia gene complex may eventually contribute to this effect. We suggest, therefore, that screening programs for heterozygous beta-thalassemia in populations where alpha-thalassemia is also prevalent, should incorporate the determination of HbA2 in the first set of tests.

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