scholarly journals Alpha-thalassemia in two Mediterranean populations

Blood ◽  
1982 ◽  
Vol 60 (2) ◽  
pp. 509-512
Author(s):  
M Pirastu ◽  
KY Lee ◽  
AM Dozy ◽  
YW Kan ◽  
G Stamatoyannopoulos ◽  
...  
Keyword(s):  
Population Sample ◽  
Restriction Endonuclease Analysis ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Mediterranean Islands ◽  
Mediterranean Populations ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Greek Cypriots ◽  
Endonuclease Analysis

We used restriction endonuclease analysis to determine the incidence of alpha-thalassemia in two Mediterranean islands. In a random population sample, the gene frequency of deletion-type alpha-thalassemia-2 (- alpha) was 0.18 in Sardinians and 0.07 in Greek Cypriots. All cases were the rightward crossover type. From these frequencies and the known incidence of hemoglobin-H disease in these populations, we calculated the frequency of the alpha-thalassemia-1 genotype (--) and determined that it was low. We also found that beta-thalassemia homozygotes in sardinia have a higher incidence of alpha-thalassemia than normals and beta thalassemia heterozygotes because a significantly greater number of these homozygotes are also homozygous for the alpha-thalassemia-2 lesion. These findings support the theory that coinheritance of alpha- thalassemia mitigates the severity of beta-thalassemia and suggest that the protection is most pronounced when two alpha-globin genes are deleted.

scholarly journals Alpha-thalassemia in two Mediterranean populations

Blood ◽  
1982 ◽  
Vol 60 (2) ◽  
pp. 509-512 ◽  
Author(s):  
M Pirastu ◽  
KY Lee ◽  
AM Dozy ◽  
YW Kan ◽  
G Stamatoyannopoulos ◽  
...  
Keyword(s):  
Population Sample ◽  
Restriction Endonuclease Analysis ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Mediterranean Islands ◽  
Mediterranean Populations ◽  
Alpha Thalassemia ◽  
Alpha Globin ◽  
Greek Cypriots ◽  
Endonuclease Analysis

Abstract We used restriction endonuclease analysis to determine the incidence of alpha-thalassemia in two Mediterranean islands. In a random population sample, the gene frequency of deletion-type alpha-thalassemia-2 (- alpha) was 0.18 in Sardinians and 0.07 in Greek Cypriots. All cases were the rightward crossover type. From these frequencies and the known incidence of hemoglobin-H disease in these populations, we calculated the frequency of the alpha-thalassemia-1 genotype (--) and determined that it was low. We also found that beta-thalassemia homozygotes in sardinia have a higher incidence of alpha-thalassemia than normals and beta thalassemia heterozygotes because a significantly greater number of these homozygotes are also homozygous for the alpha-thalassemia-2 lesion. These findings support the theory that coinheritance of alpha- thalassemia mitigates the severity of beta-thalassemia and suggest that the protection is most pronounced when two alpha-globin genes are deleted.

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 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

Abstract 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 Beta zero-thalassemia in association with a gamma-globin gene quadruplication

Blood ◽  
1986 ◽  
Vol 68 (6) ◽  
pp. 1394-1397
Author(s):  
KG Yang ◽  
JZ Liu ◽  
F Kutlar ◽  
A Kutlar ◽  
C Altay ◽  
...  
Keyword(s):  
Clinical Condition ◽  
Globin Gene ◽  
Normal Chromosome ◽  
Gene Arrangement ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Thalassemia Intermedia ◽  
Gamma Globin ◽  
Alpha Globin

We have studied the hematology, hemoglobin composition, and globin gene arrangements in one young Turkish boy with a beta zero-thalassemia homozygosity and in 11 of his relatives. Evidence is presented that the chromosome with the beta zero-thalassemia determinant carries a gamma- globin gene quadruplication, perhaps in a -G gamma-G gamma-G gamma-A gamma-gene arrangement. The eight gamma-globin genes in this patient produced G gamma and A gamma chains in a 95 to 5 ratio, and nearly 99% of the patient's hemoglobin was of the fetal type. The clinical condition resembled that of a thalassemia intermedia. HbF levels in eight beta-thalassemia heterozygotes varied between 0.5 and 4.2% and the percentages of G gamma in this HbF averaged at 87% or 95%; this level is to some extent related to the haplotype of the normal chromosome. All subjects carried four alpha-globin genes; a new BglII polymorphism was observed within the psi alpha-globin gene.

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 Delineation of specific beta-thalassemia mutations in high-risk areas of Italy: a prerequisite for prenatal diagnosis

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 983-988 ◽  
Author(s):  
M Pirastu ◽  
G Saglio ◽  
C Camaschella ◽  
A Loi ◽  
A Serra ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Dna Analysis ◽  
Restriction Endonuclease Analysis ◽  
Beta Thalassemia ◽  
Italian Population ◽  
Oligonucleotide Hybridization ◽  
Frequent Mutations ◽  
Risk Areas ◽  
Compound Heterozygotes ◽  
Endonuclease Analysis

Abstract In this study, we defined by haplotype characterization combined with oligonucleotide hybridization or direct restriction endonuclease analysis the specific beta-thalassemia mutations in a representative sample of beta-thalassemia chromosomes from patients with homozygous beta-thalassemia originating from different parts of Italy. We characterized the mutations in 90% of the thalassemia chromosomes and found that three mutations, namely the beta+IVS 1–110, beta degrees -39 and beta+IVS 1–6 are prevalent in the Italian population. Most of the patients investigated were compound heterozygotes for two beta- thalassemia mutations, and only a few were homozygotes for one mutant. On the basis of these findings, we predict that prenatal diagnosis in this population would be feasible in most cases by fetal DNA analysis with the oligonucleotide method using a limited number of oligonucleotide probes selected after screening parents for the most common beta-thalassemia mutations. We have also devised a method based on hybridization with a mixture of two oligonucleotides that allows rapid and simultaneous screening of prospective parents for the two most frequent mutations in Italians, the beta+IVS 1–110 and beta degrees -39 mutants. This method may be applicable to prenatal diagnosis in cases at risk for the genetic compound of these mutations.

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.

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 Suppression of human alpha-globin gene expression mediated by the recombinant adeno-associated virus 2-based antisense vectors.

1994 ◽  
Vol 179 (2) ◽  
pp. 733-738 ◽  
Author(s):  
S Ponnazhagan ◽  
M L Nallari ◽  
A Srivastava
Keyword(s):  
Globin Gene ◽  
Gene Promoter ◽  
Early Gene ◽  
Beta Thalassemia ◽  
Transcriptional Level ◽  
Globin Genes ◽  
Antisense Gene ◽  
Adeno Associated Virus ◽  
Bacterial Gene ◽  
Alpha Globin

We sought to investigate the usefulness of the adeno-associated virus 2 (AAV)-based vectors to suppress the excess production of the human alpha-globin gene product towards developing a treatment modality for beta-thalassemia since accumulation of free alpha-globin reduces the lifespan of red blood cells in these patients. We constructed recombinant AAV virions containing the human alpha-globin gene sequences in antisense orientation driven by the herpesvirus thymidine kinase (TK) promoter, the SV40 early gene promoter, and the human alpha-globin gene promoter, respectively, as well as a bacterial gene for resistance to neomycin (neoR) as a selectable marker. These recombinant virions were used to infect a human erythroleukemia cell line (K562) that express high levels of alpha-globin mRNA. Clonal populations of neoR cells were obtained after selection with the drug G418, a neomycin analogue. Total genomic DNA samples isolated from these cells were analyzed on Southern blots to document stable integration of the transduced neo and alpha-globin genes. Total cellular RNA samples isolated from mock-infected and recombinant virus-infected cultures were also analyzed by Northern blots. Whereas the TK promoter-driven antisense alpha-globin sequences showed no inhibition of expression of the endogenous alpha-globin gene, the SV40 promoter and the alpha-globin gene promoter-driven antisense alpha-globin sequences suppressed the expression of this constitutively over-expressed gene by approximately 29 and 91%, respectively, at the transcriptional level. These studies suggest the feasibility of utilizing the AAV-based antisense gene transfer approach in the potential treatment of beta-thalassemia.

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