scholarly journals Molecular characterization of a beta zero-thalassemia resulting from a 1.4 kilobase deletion

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 636-641 ◽  
Author(s):  
R Anand ◽  
CD Boehm ◽  
HH Jr Kazazian ◽  
EF Vanin
Keyword(s):  
Transcriptional Start Site ◽  
Globin Gene ◽  
Event Analysis ◽  
Beta Globin ◽  
Base Pairs ◽  
Dna Polymerase Alpha ◽  
Beta Globin Gene ◽  
American Black ◽  
The Individual

Abstract We report the characterization of a beta zero-thalassemia in an American Black with unusually high HbA2 and HbF levels. Genomic southern analysis indicated that the individual was heterozygous for a deletion that began within the second intervening sequence of the beta- globin gene and extended approximately 1.4 kb in the 5′ direction. A clone spanning the breakpoint on the abnormal chromosome was isolated and further mapped, and the deletion joint was sequenced. Comparison of the normal beta-globin gene and its 5′ flanking region with the deletion joint sequence indicated that the 5′ breakpoint for this deletion was 484 base pairs (bp) 5′ to the transcriptional start site for the beta-globin gene and the 3′ breakpoint was 908 bp into the beta- globin gene; the deletion removed a total of 1,393 bp. Comparison of the normal 5′ and 3′ breakpoint sequences indicated that this deletion was the result of a “clean” nonhomologous breakage and reunion event; ie, no spurious bases were added during the recombinational event. Analysis of the breakpoints of this deletion together with the breakpoints of two other small deletions involving the beta-globin gene suggests that the breakpoints may occur at DNA polymerase alpha pause sites.

scholarly journals Molecular characterization of a beta zero-thalassemia resulting from a 1.4 kilobase deletion

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 636-641
Author(s):  
R Anand ◽  
CD Boehm ◽  
HH Jr Kazazian ◽  
EF Vanin
Keyword(s):  
Transcriptional Start Site ◽  
Globin Gene ◽  
Event Analysis ◽  
Beta Globin ◽  
Base Pairs ◽  
Dna Polymerase Alpha ◽  
Beta Globin Gene ◽  
American Black ◽  
The Individual

We report the characterization of a beta zero-thalassemia in an American Black with unusually high HbA2 and HbF levels. Genomic southern analysis indicated that the individual was heterozygous for a deletion that began within the second intervening sequence of the beta- globin gene and extended approximately 1.4 kb in the 5′ direction. A clone spanning the breakpoint on the abnormal chromosome was isolated and further mapped, and the deletion joint was sequenced. Comparison of the normal beta-globin gene and its 5′ flanking region with the deletion joint sequence indicated that the 5′ breakpoint for this deletion was 484 base pairs (bp) 5′ to the transcriptional start site for the beta-globin gene and the 3′ breakpoint was 908 bp into the beta- globin gene; the deletion removed a total of 1,393 bp. Comparison of the normal 5′ and 3′ breakpoint sequences indicated that this deletion was the result of a “clean” nonhomologous breakage and reunion event; ie, no spurious bases were added during the recombinational event. Analysis of the breakpoints of this deletion together with the breakpoints of two other small deletions involving the beta-globin gene suggests that the breakpoints may occur at DNA polymerase alpha pause sites.

Upstream G gamma-globin and downstream beta-globin sequences required for stage-specific expression in transgenic mice

1987 ◽  
Vol 7 (11) ◽  
pp. 4024-4029
Author(s):  
M Trudel ◽  
J Magram ◽  
L Bruckner ◽  
F Costantini
Keyword(s):  
Transgenic Mice ◽  
Fusion Gene ◽  
Globin Gene ◽  
Regulatory Elements ◽  
Globin Genes ◽  
Beta Globin ◽  
Erythroid Cells ◽  
Base Pairs ◽  
Beta Globin Gene ◽  
Gamma Globin

The human G gamma-globin and beta-globin genes are expressed in erythroid cells at different stages of human development, and previous studies have shown that the two cloned genes are also expressed in a differential stage-specific manner in transgenic mice. The G gamma-globin gene is expressed only in murine embryonic erythroid cells, while the beta-globin gene is active only at the fetal and adult stages. In this study, we analyzed transgenic mice carrying a series of hybrid genes in which different upstream, intragenic, or downstream sequences were contributed by the beta-globin or G gamma-globin gene. We found that hybrid 5'G gamma/3'beta globin genes containing G gamma-globin sequences upstream from the initiation codon were expressed in embryonic erythroid cells at levels similar to those of an intact G gamma-globin transgene. In contrast, beta-globin upstream sequences were insufficient for expression of 5'beta/3'G gamma hybrid globin genes or a beta-globin-metallothionein fusion gene in adult erythroid cells. However, beta-globin downstream sequences, including 212 base pairs of exon III and 1,900 base pairs of 3'-flanking DNA, were able to activate a 5'G gamma/3'beta hybrid globin gene in fetal and adult erythroid cells. These experiments suggest that positive regulatory elements upstream from the G gamma-globin and downstream from the beta-globin gene are involved in the differential expression of the two genes during development.

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

Blood ◽  
1984 ◽  
Vol 64 (4) ◽  
pp. 941-944 ◽  
Author(s):  
BJ Padanilam ◽  
AE Felice ◽  
TH Huisman
Keyword(s):  
Black Family ◽  
Globin Gene ◽  
Splice Junction ◽  
Beta Globin ◽  
Partial Deletion ◽  
Beta Globin Gene ◽  
American Patient ◽  
Thalassemia Trait ◽  
American Black ◽  
Endonuclease Mapping

Abstract Restriction endonuclease mapping defined a partial deletion of about 1.35 kb in the beta-globin gene of a black American patient with hemoglobin S-beta zero-thalassemia and in his uncle with a beta zero- thalassemia trait. The 5′ endpoint of the deletion is about 600 bases upstream from the cap site, and the 3′ endpoint lies within about 500 bases from the 5 splice junction of the second intervening sequence. The deletion is different from that of a previously reported Indian beta zero-thalassemia allele, where 0.6 kb is deleted at the 3′ end of the beta-globin gene.

scholarly journals Beta thalassemia in Melanesia: association with malaria and characterization of a common variant (IVS-1 nt 5 G----C)

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 9-14 ◽  
Author(s):  
AV Hill ◽  
DK Bowden ◽  
DF O'Shaughnessy ◽  
DJ Weatherall ◽  
JB Clegg
Keyword(s):  
Oligonucleotide Probe ◽  
Globin Gene ◽  
Plasmid Vector ◽  
New Guinea ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Intron 1 ◽  
High Incidence

Data on the distribution of beta thalassemia among over 6,000 Melanesians reveals a major difference in the carrier rates between populations in the malarious coastal regions of New Guinea and those living in the historically malaria-free Highlands. The island of Maewo in Vanuatu has a particularly high incidence of beta + thalassemia associated with a single restriction enzyme haplotype. Direct cloning into a plasmid vector and sequence analysis demonstrate that the mutation is a G to C transversion at position 5 of intron 1 of the beta- globin gene. Oligonucleotide probe surveys indicate that this variant accounted for all cases of beta thalassemia studied from Maewo. It is also common in coastal Papua New Guinea where haplotype and oligonucleotide probe data suggest that the molecular basis of beta thalassmia is more heterogeneous.

scholarly journals Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant

Blood ◽  
1991 ◽  
Vol 77 (4) ◽  
pp. 861-867
Author(s):  
M Losekoot ◽  
R Fodde ◽  
EJ Gerritsen ◽  
I van de Kuit ◽  
A Schreuder ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Globin ◽  
Gamma Delta ◽  
Hemoglobin F ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Hereditary Persistence

We report two different disorders of the beta-globin gene cluster segregating in a Belgian family: a novel deletion that results in (G) gamma + ((A) gamma delta beta)(0)-thalassemia (thal) and a heterocellular hereditary persistence of foetal hemoglobin of the Swiss type linked to a delta(0)-thal gene (delta (0)-HPFH). Heterozygosity for the heterocellular HPFH brings about a moderate (3.4% to 8.24%) increase of hemoglobin (Hb) F having a G gamma/A gamma ratio of 4:1, whereas carriers of the G gamma + ((A) gamma delta beta)(0)-thal deletion show in their peripheral blood a considerably higher (15%) percentage of Hb F. Both defects interact in the compound heterozygotes for G gamma + ((A) gamma delta beta)(0)-thal and delta(0)-HPFH producing a further increase (up to 24%) of fetal Hb consisting entirely of G gamma chains. Molecular characterization of the (G) gamma + ((A) gamma delta beta)(0)-thal by means of Southern analysis showed that the deletion spans about 50 kb, removing the 3′ end of the A gamma- gene, the psi beta-, delta-, and beta-genes. A number of possible mechanisms leading to the overproduction of Hb F in HPFH and (G) gamma + ((A) gamma delta beta)(0)-thal will be discussed.

scholarly journals Molecular and hematologic characterization of Scottish-Irish type (epsilon gamma delta beta)zero thalassemia

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2132-2138
Author(s):  
RJ Trent ◽  
BG Williams ◽  
A Kearney ◽  
T Wilkinson ◽  
PC Harris
Keyword(s):  
Dna Sequence ◽  
Globin Gene ◽  
Globin Genes ◽  
The Novel ◽  
Beta Globin ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Clinical Phenotypes ◽  
Dna Deletion

The DNA deletion associated with an example of (epsilon gamma delta beta)zero thalassemia (Scottish-Irish type) was characterized. The deletion is approximately 205 kb in length and involves the epsilon, G gamma, A gamma, delta, and beta globin genes. The breakpoint is located 263 bp 3′ to exon 3 of the beta globin gene. An LI (KpnI) repeat element approximately 320 bp in size is found at the 3′ end of the novel DNA sequence. Different clinical phenotypes for three heterozygous neonates suggest that the deletion alone does not predict severity of (epsilon gamma delta beta)zero thalassemia at this age.

scholarly journals Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant

Blood ◽  
1991 ◽  
Vol 77 (4) ◽  
pp. 861-867 ◽  
Author(s):  
M Losekoot ◽  
R Fodde ◽  
EJ Gerritsen ◽  
I van de Kuit ◽  
A Schreuder ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Globin ◽  
Gamma Delta ◽  
Hemoglobin F ◽  
Beta Globin Gene ◽  
Globin Gene Cluster ◽  
Hereditary Persistence

Abstract We report two different disorders of the beta-globin gene cluster segregating in a Belgian family: a novel deletion that results in (G) gamma + ((A) gamma delta beta)(0)-thalassemia (thal) and a heterocellular hereditary persistence of foetal hemoglobin of the Swiss type linked to a delta(0)-thal gene (delta (0)-HPFH). Heterozygosity for the heterocellular HPFH brings about a moderate (3.4% to 8.24%) increase of hemoglobin (Hb) F having a G gamma/A gamma ratio of 4:1, whereas carriers of the G gamma + ((A) gamma delta beta)(0)-thal deletion show in their peripheral blood a considerably higher (15%) percentage of Hb F. Both defects interact in the compound heterozygotes for G gamma + ((A) gamma delta beta)(0)-thal and delta(0)-HPFH producing a further increase (up to 24%) of fetal Hb consisting entirely of G gamma chains. Molecular characterization of the (G) gamma + ((A) gamma delta beta)(0)-thal by means of Southern analysis showed that the deletion spans about 50 kb, removing the 3′ end of the A gamma- gene, the psi beta-, delta-, and beta-genes. A number of possible mechanisms leading to the overproduction of Hb F in HPFH and (G) gamma + ((A) gamma delta beta)(0)-thal will be discussed.

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