Alpha-thalassemia caused by a large (62 kb) deletion upstream of the human alpha globin gene cluster

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 221-227
Author(s):  
CS Hatton ◽  
AO Wilkie ◽  
HC Drysdale ◽  
WG Wood ◽  
MA Vickers ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Dna Sequence ◽  
Interspecific Hybrid ◽  
Globin Gene ◽  
Regulatory Sequences ◽  
Globin Genes ◽  
Beta Globin ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Globin Synthesis

We describe a family in which alpha-thalassemia occurs in association with a deletion of 62 kilobases from a region upstream of the alpha globin genes. DNA sequence analysis has shown that the transcription units of both alpha genes downstream of this deletion are normal. Nevertheless, they fail to direct alpha globin synthesis in an interspecific hybrid containing the abnormal (alpha alpha)RA chromosome. It seems probable that previously unidentified positive regulatory sequences analogous to those detected in a corresponding position of the human beta globin cluster are removed by this deletion.

scholarly journals Alpha-thalassemia caused by a large (62 kb) deletion upstream of the human alpha globin gene cluster

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 221-227 ◽  
Author(s):  
CS Hatton ◽  
AO Wilkie ◽  
HC Drysdale ◽  
WG Wood ◽  
MA Vickers ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Dna Sequence ◽  
Interspecific Hybrid ◽  
Globin Gene ◽  
Regulatory Sequences ◽  
Globin Genes ◽  
Beta Globin ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Globin Synthesis

Abstract We describe a family in which alpha-thalassemia occurs in association with a deletion of 62 kilobases from a region upstream of the alpha globin genes. DNA sequence analysis has shown that the transcription units of both alpha genes downstream of this deletion are normal. Nevertheless, they fail to direct alpha globin synthesis in an interspecific hybrid containing the abnormal (alpha alpha)RA chromosome. It seems probable that previously unidentified positive regulatory sequences analogous to those detected in a corresponding position of the human beta globin cluster are removed by this 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.

A silencer element from the alpha-globin gene inhibits expression of beta-like genes

1988 ◽  
Vol 8 (11) ◽  
pp. 5047-5051
Author(s):  
G F Atweh ◽  
J M Liu ◽  
H E Brickner ◽  
X X Zhu
Keyword(s):  
Globin Gene ◽  
Expression System ◽  
Globin Genes ◽  
Beta Globin ◽  
Base Pair Fragment ◽  
Alpha Globin ◽  
In Trans ◽  
Cis And Trans ◽  
In Cis ◽  
Silencer Element

We have studied the cis and trans interactions of the alpha- and beta-globin genes in a transient expression system. We found that the alpha-globin gene inhibited beta-globin expression in cis but not in trans. The silencer element responsible for this inhibition was localized to a 259-base-pair fragment at the 5' end of the alpha-globin gene.

scholarly journals An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age

Blood ◽  
1995 ◽  
Vol 85 (4) ◽  
pp. 1111-1117 ◽  
Author(s):  
YC Chang ◽  
KD Smith ◽  
RD Moore ◽  
GR Serjeant ◽  
GJ Dover
Keyword(s):  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Beta Globin ◽  
Gene Number ◽  
Cohort Group ◽  
Five Factors ◽  
F Cells ◽  
Alpha Globin

Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a Cohort group identified by newborn screening and from a Sib Pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < .05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation. The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s).

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.

scholarly journals Developmental switch in the relative expression of the alpha 1- and alpha 2-globin genes in humans and in transgenic mice

Blood ◽  
1992 ◽  
Vol 79 (9) ◽  
pp. 2471-2474 ◽  
Author(s):  
M Albitar ◽  
FE Cash ◽  
C Peschle ◽  
SA Liebhaber
Keyword(s):  
Transgenic Mice ◽  
Globin Gene ◽  
Gene Activation ◽  
Experimental System ◽  
Gene Clusters ◽  
Globin Genes ◽  
Beta Globin ◽  
Relative Expression ◽  
Structural Identity ◽  
Alpha Globin

Abstract Human alpha-globin is encoded by two adjacent genes, alpha 2 and alpha 1. Despite their remarkable level of structural identity, the more 5′ (alpha 2) gene is the major alpha-globin locus in the normal adult, expressed at 2.6-fold higher levels than the adjacent and more 3′ (alpha 1) globin gene. In light of the well-characterized pattern of gene activation in the human alpha- and beta-globin gene clusters during development, we considered the possibility that the relative expression of these two alpha-globin loci might be developmentally controlled. Analysis of human embryonic and early fetal erythroid RNA samples confirmed this possibility; levels of mRNA encoded by the two alpha-globin loci are equal in the embryo and subsequently shift to dominant expression of the alpha 2-globin locus at week 8 in utero. In transgenic mice carrying the entire human alpha-globin cluster (except for the theta gene) we show the same shift from equal expression of the alpha 1- and alpha 2-globin loci at the embryonic stage to predominance of the alpha 2-globin locus in the adult. These data demonstrate a switch in the expression of the two adjacent alpha-globin genes during the embryonic-to-fetal switch in erythroid development and provide an experimental system for its further characterization.

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.

scholarly journals DNA sequence variation in a negative control region 5' to the beta- globin gene correlates with the phenotypic expression of the beta s mutation

Blood ◽  
1992 ◽  
Vol 79 (3) ◽  
pp. 787-792 ◽  
Author(s):  
J Elion ◽  
PE Berg ◽  
C Lapoumeroulie ◽  
G Trabuchet ◽  
M Mittelman ◽  
...  
Keyword(s):  
Dna Sequence ◽  
Sickle Cell ◽  
Globin Gene ◽  
Phenotypic Expression ◽  
Fetal Hemoglobin ◽  
Negative Control ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Hb S

The clinical diversity of sickle cell anemia is strongly related to the degree of intracellular hemoglobin S (Hb S) polymerization, which in turn is dependent on the intracellular concentration of Hb S. We have recently defined a region of DNA approximately 500 bp 5′ to the human beta-globin gene that acts as a silencer for the transcription of this gene and have shown that a polymorphism in this sequence is associated with a thalassemic phenotype of the beta-globin gene. In this work we have examined the correlation of DNA sequence polymorphisms in this silencer with binding of a previously identified putative repressor protein, BP1, and with the expression of Hb S in individuals heterozygous for the beta s allele. It was found that specific configurations of the motif, (AT)x(T)y, are homogeneous for the major haplotypes of the beta-globin gene cluster described on beta s chromosomes. Binding of BP1 was measured to DNA of three haplotypes: Indian, Benin, and Bantu. BP1 binds most tightly to DNA of the Indian haplotype, and these patients produce less beta s protein than Benin patients, whose DNA exhibits weaker affinity for BP1. Binding of BP1 is the weakest to DNA of the Bantu haplotype, which is associated with clinically more severe sickle cell symptoms. These data are consistent with the hypothesis that these polymorphisms may not be neutral and that the DNA sequence at this site may affect the expression of the beta s gene. Such an effect may be synergistic with other genetic variables, such as fetal hemoglobin levels, F-cell numbers, and the number of alpha-globin genes, in determining intracellular polymerization and, thus, the severity of the sickle cell syndromes.

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