scholarly journals A new hereditary persistence of fetal hemoglobin deletion has the breakpoint within the 3' beta-globin gene enhancer

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 1000-1005
Author(s):  
C Camaschella ◽  
A Serra ◽  
E Gottardi ◽  
A Alfarano ◽  
D Revello ◽  
...  
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Enhancer Element ◽  
Beta Globin Gene ◽  
Gene Enhancer ◽  
Molecular Comparison ◽  
Hereditary Persistence ◽  
Endonuclease Mapping

A new deletion of the beta-globin gene cluster has been characterized in two Italian brothers who are heterozygous carriers of a G gamma A gamma hereditary persistence of fetal hemoglobin (HPFH). Restriction endonuclease mapping and DNA sequencing of the region encompassing the breakpoint show that the deletion starts 3.2 kilobases (kb) upstream from the delta gene and ends within the enhancer region 3′ to the beta- globin gene. Here the deletion removes one of the four binding sites for an erythroid specific transcriptional factor (NF-E1). The molecular comparison of the new deletion with others of similar size and location but associated with a delta beta-thalassemia phenotype suggests that the residual enhancer element, relocated near gamma genes, may increase the fetal hemoglobin (HbF) expression above the level observed in delta beta-thalassemia.

scholarly journals A new hereditary persistence of fetal hemoglobin deletion has the breakpoint within the 3' beta-globin gene enhancer

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 1000-1005 ◽  
Author(s):  
C Camaschella ◽  
A Serra ◽  
E Gottardi ◽  
A Alfarano ◽  
D Revello ◽  
...  
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Enhancer Element ◽  
Beta Globin Gene ◽  
Gene Enhancer ◽  
Molecular Comparison ◽  
Hereditary Persistence ◽  
Endonuclease Mapping

Abstract A new deletion of the beta-globin gene cluster has been characterized in two Italian brothers who are heterozygous carriers of a G gamma A gamma hereditary persistence of fetal hemoglobin (HPFH). Restriction endonuclease mapping and DNA sequencing of the region encompassing the breakpoint show that the deletion starts 3.2 kilobases (kb) upstream from the delta gene and ends within the enhancer region 3′ to the beta- globin gene. Here the deletion removes one of the four binding sites for an erythroid specific transcriptional factor (NF-E1). The molecular comparison of the new deletion with others of similar size and location but associated with a delta beta-thalassemia phenotype suggests that the residual enhancer element, relocated near gamma genes, may increase the fetal hemoglobin (HbF) expression above the level observed in delta beta-thalassemia.

scholarly journals The 18- to 23-kb deletion of the Macedonian delta beta-thalassemia includes the entire delta and beta globin genes

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 971-974
Author(s):  
GD Efremov ◽  
N Nikolov ◽  
Y Hattori ◽  
I Bakioglu ◽  
TH Huisman
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Large Deletion ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Restriction Sites ◽  
Endonuclease Mapping

Restriction endonuclease mapping analyses were made of DNA from a few members of a Macedonian family with hematological characteristics of delta beta-thalassemia, ie, microcytosis, normal HbA2 levels, and elevated levels of HbF (7% to 14%) with G gamma (average 40.5%) and A gamma T chains (average 59.5%). A large deletion of 18 to 23 kb was present with a 5′ breakpoint within a 670-bp segment of DNA between the HpaI and NcoI restriction sites 5′ to the delta globin gene, and a 3′ breakpoint between the BamHI and HpaI restriction sites located some 9 to 13 kb 3′ to the beta globin gene. This deletion is different from those present in other types of G gamma A gamma(delta beta)zero- thalassemia. The similarity of the hematological expression of these delta beta-thalassemic conditions which have somewhat comparable 5′ breakpoints supports the idea that an important fetal hemoglobin- controlling region lies between the psi beta and delta globin genes.

scholarly journals The 18- to 23-kb deletion of the Macedonian delta beta-thalassemia includes the entire delta and beta globin genes

Blood ◽  
1986 ◽  
Vol 68 (4) ◽  
pp. 971-974 ◽  
Author(s):  
GD Efremov ◽  
N Nikolov ◽  
Y Hattori ◽  
I Bakioglu ◽  
TH Huisman
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Large Deletion ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Restriction Sites ◽  
Endonuclease Mapping

Abstract Restriction endonuclease mapping analyses were made of DNA from a few members of a Macedonian family with hematological characteristics of delta beta-thalassemia, ie, microcytosis, normal HbA2 levels, and elevated levels of HbF (7% to 14%) with G gamma (average 40.5%) and A gamma T chains (average 59.5%). A large deletion of 18 to 23 kb was present with a 5′ breakpoint within a 670-bp segment of DNA between the HpaI and NcoI restriction sites 5′ to the delta globin gene, and a 3′ breakpoint between the BamHI and HpaI restriction sites located some 9 to 13 kb 3′ to the beta globin gene. This deletion is different from those present in other types of G gamma A gamma(delta beta)zero- thalassemia. The similarity of the hematological expression of these delta beta-thalassemic conditions which have somewhat comparable 5′ breakpoints supports the idea that an important fetal hemoglobin- controlling region lies between the psi beta and delta globin genes.

scholarly journals Rapid detection of deletions causing delta beta thalassemia and hereditary persistence of fetal hemoglobin by enzymatic amplification

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1673-1682 ◽  
Author(s):  
JE Craig ◽  
RA Barnetson ◽  
J Prior ◽  
JL Raven ◽  
SL Thein
Keyword(s):  
Asian Indian ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Chromosome 11 ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Enzymatic Amplification ◽  
Hereditary Persistence

Abstract A considerable number of deletions of variable size and position that involve the beta-globin gene complex on chromosome 11 are associated with the clinical entities of hereditary persistence of fetal hemoglobin (HPFH) and delta beta thalassemia. Specific deletions appear to be associated with consistent phenotypes and some are known to be recurrent. To facilitate the molecular diagnosis of uncharacterized patients with HPFH and delta beta thalassemia, oligonucleotide primers have been designed to enzymatically amplify deletion-specific products for nine known deletions, which include those responsible for HPFH-1, HPFH-2, HPFH-3, Spanish (delta beta)zero thalassemia, hemoglobin (Hb) Lepore, Sicilian (delta beta)zero thalassemia, Chinese G gamma(A gamma delta beta)zero thalassemia, Asian-Indian inversion-deletion G gamma(A gamma delta beta)zero thalassemia, and Turkish inversion-deletion (delta beta)zero thalassemia. Using this approach, we have successfully characterized the molecular basis for delta beta thalassemia in 23 individuals from 16 families of diverse ethnic origins. Thirteen individuals from this group were shown to be heterozygous for the 13.4- kb Sicilian deletion, two were heterozygous for the 100-kb Chinese G gamma(A gamma delta beta)zero deletion, four were heterozygous for the Turkish form of inversion-deletion delta beta thalassemia, and three were heterozygous for the Asian-Indian form of inversion-deletion G gamma(A gamma delta beta)zero thalassemia. One Vietnamese subject was heterozygous for a 12.6-kb deletion, which we have fully characterized at the molecular level. Sequence analysis of the breakpoint regions of the Chinese deletion and the Turkish rearrangement indicates that, in each case, the mutation is likely to have arisen from a single origin. This hypothesis is supported by the evident geographical clustering of the various deletions described here.

scholarly journals Rapid detection of deletions causing delta beta thalassemia and hereditary persistence of fetal hemoglobin by enzymatic amplification

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1673-1682
Author(s):  
JE Craig ◽  
RA Barnetson ◽  
J Prior ◽  
JL Raven ◽  
SL Thein
Keyword(s):  
Asian Indian ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Chromosome 11 ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Enzymatic Amplification ◽  
Hereditary Persistence

A considerable number of deletions of variable size and position that involve the beta-globin gene complex on chromosome 11 are associated with the clinical entities of hereditary persistence of fetal hemoglobin (HPFH) and delta beta thalassemia. Specific deletions appear to be associated with consistent phenotypes and some are known to be recurrent. To facilitate the molecular diagnosis of uncharacterized patients with HPFH and delta beta thalassemia, oligonucleotide primers have been designed to enzymatically amplify deletion-specific products for nine known deletions, which include those responsible for HPFH-1, HPFH-2, HPFH-3, Spanish (delta beta)zero thalassemia, hemoglobin (Hb) Lepore, Sicilian (delta beta)zero thalassemia, Chinese G gamma(A gamma delta beta)zero thalassemia, Asian-Indian inversion-deletion G gamma(A gamma delta beta)zero thalassemia, and Turkish inversion-deletion (delta beta)zero thalassemia. Using this approach, we have successfully characterized the molecular basis for delta beta thalassemia in 23 individuals from 16 families of diverse ethnic origins. Thirteen individuals from this group were shown to be heterozygous for the 13.4- kb Sicilian deletion, two were heterozygous for the 100-kb Chinese G gamma(A gamma delta beta)zero deletion, four were heterozygous for the Turkish form of inversion-deletion delta beta thalassemia, and three were heterozygous for the Asian-Indian form of inversion-deletion G gamma(A gamma delta beta)zero thalassemia. One Vietnamese subject was heterozygous for a 12.6-kb deletion, which we have fully characterized at the molecular level. Sequence analysis of the breakpoint regions of the Chinese deletion and the Turkish rearrangement indicates that, in each case, the mutation is likely to have arisen from a single origin. This hypothesis is supported by the evident geographical clustering of the various deletions described here.

scholarly journals Molecular analysis of Japanese delta beta-thalassemia

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1771-1776
Author(s):  
S Shiokawa ◽  
H Yamada ◽  
Y Takihara ◽  
E Matsunaga ◽  
Y Ohba ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Large Deletions ◽  
Deletion Junction

A DNA fragment containing the deletion junction region from a Japanese individual with homozygous delta beta-thalassemia has been cloned. A clone containing the normal DNA surrounding the 3′ breakpoint of this deletion and a clone carrying the G gamma- and A gamma-globin genes of this patient were also isolated. Sequences of the deletion junction and both gamma-globin genes were determined. A comparison of these sequences with previously determined sequences of the normal counterparts revealed that the 5′ breakpoint is located between 2,134 and 2,137 base pairs (bp) 3′ to the polyA site of the A gamma-globin gene, the 5′ breakpoint is located just downstream of the 3′ border of the fetal gamma-globin duplication unit, and no molecular defects are evident within the gamma-globin gene region. A comparison between the sequences of the normal DNA surrounding the 3′ breakpoint and the normal DNA surrounding the 5′ breakpoint shows that deletion is the result of a nonhomologous recombination event. There are A+T-rich stretches near the 5′ and 3′ breakpoints in the normal DNA, and a portion of an Aly repeat is located in the region 3′ to the 3′ breakpoint. Southern blot analysis using probes 3′ to the beta-globin gene showed that the deletion extends in the 3′ direction further than any other deletions associated with delta beta-thalassemia and hereditary persistence of fetal hemoglobin (HPFH) heretofore reported. These results are discussed in terms of the mechanism generating large deletions in mammalian cells and three models for the regulation of gamma-globin and beta-globin gene expression in humans.

scholarly journals Molecular analysis of Japanese delta beta-thalassemia

Blood ◽  
1988 ◽  
Vol 72 (5) ◽  
pp. 1771-1776 ◽  
Author(s):  
S Shiokawa ◽  
H Yamada ◽  
Y Takihara ◽  
E Matsunaga ◽  
Y Ohba ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Large Deletions ◽  
Deletion Junction

Abstract A DNA fragment containing the deletion junction region from a Japanese individual with homozygous delta beta-thalassemia has been cloned. A clone containing the normal DNA surrounding the 3′ breakpoint of this deletion and a clone carrying the G gamma- and A gamma-globin genes of this patient were also isolated. Sequences of the deletion junction and both gamma-globin genes were determined. A comparison of these sequences with previously determined sequences of the normal counterparts revealed that the 5′ breakpoint is located between 2,134 and 2,137 base pairs (bp) 3′ to the polyA site of the A gamma-globin gene, the 5′ breakpoint is located just downstream of the 3′ border of the fetal gamma-globin duplication unit, and no molecular defects are evident within the gamma-globin gene region. A comparison between the sequences of the normal DNA surrounding the 3′ breakpoint and the normal DNA surrounding the 5′ breakpoint shows that deletion is the result of a nonhomologous recombination event. There are A+T-rich stretches near the 5′ and 3′ breakpoints in the normal DNA, and a portion of an Aly repeat is located in the region 3′ to the 3′ breakpoint. Southern blot analysis using probes 3′ to the beta-globin gene showed that the deletion extends in the 3′ direction further than any other deletions associated with delta beta-thalassemia and hereditary persistence of fetal hemoglobin (HPFH) heretofore reported. These results are discussed in terms of the mechanism generating large deletions in mammalian cells and three models for the regulation of gamma-globin and beta-globin gene expression in humans.

scholarly journals Eastern European (delta beta) zero-thalassemia: molecular characterization of a novel 9.1-kb deletion resulting in high levels of fetal hemoglobin in the adult [see comments]

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3738-3745 ◽  
Author(s):  
A Palena ◽  
A Blau ◽  
G Stamatoyannopoulos ◽  
NP Anagnou
Keyword(s):  
Globin Gene ◽  
Adult Life ◽  
Fetal Hemoglobin ◽  
Direct Repeat ◽  
Regulatory Elements ◽  
Negative Control ◽  
Beta Thalassemia ◽  
Eastern European ◽  
Beta Globin ◽  
Beta Globin Gene

A novel deletion in the human beta-globin gene cluster associated with increased levels of fetal hemoglobin (HbF) in adult life was molecularly characterized in a member of a family of Eastern European descent. The phenotype of the deletion, documented in five members of the family, shows mild hypochromia and microcytosis (mean corpuscular Hb, 24 to 25.9 pg; mean corpuscular volume, 74 to 78.5 fL) but high production of HbF (13% to 24%) with heterocellular distribution (36% to 86% F cells). Extensive restriction enzyme mapping of the beta-globin cluster and sequencing of the region encompassing the breakpoints showed that the deletion starts 1,612 bp upstream of the cap site of the delta-globin gene, and terminates within the first intron of the beta-globin gene, deleting 9.1 kb of DNA. This length is definitely shorter than the average 12.0 kb of the previously characterized (delta beta) zero-thalassemias. The 5′ breakpoint of the new deletion is close to that of the Yugoslavian delta beta-thalassemia deletion, whereas the 3′ breakpoint is very close to those of the Turkish and the Greek beta zero-thalassemia deletions. The breakpoints of the deletion occur within a direct repeat containing a tetranucleotide exhibiting homology to a donor-splice site, and is symmetrically flanked by a set of 13- and 14-bp homologous complementary sequences, respectively. It is likely that the deletion may be the result of an “illegitimate” or “nonhomologous” recombination event to which these two short sequences may have contributed. It is of interest that the novel deletion (9.1 kb) is comparable to the Italian HPFH-5 deletion (12.9 kb), regarding both the size and the position of the breakpoints. However, the HPFH-5 deletion includes sequences flanking the breakpoints that are preserved in the new deletion. Considering the resulting two discrete phenotypes (ie, delta beta-thalassemia v HPFH), it can be hypothesized that the deleted sequences in the Italian HPFH-5 mutation may harbor regulatory elements that exert a negative control on the gamma-globin gene expression.

scholarly journals The gamma-delta-beta-globin gene region in G gamma-beta +-hereditary persistence of fetal hemoglobin

Blood ◽  
1982 ◽  
Vol 59 (4) ◽  
pp. 828-831
Author(s):  
JF Balsley ◽  
E Rappaport ◽  
E Schwartz ◽  
S Surrey
Keyword(s):  
Globin Gene ◽  
Blot Hybridization ◽  
Fetal Hemoglobin ◽  
Restriction Enzymes ◽  
Restriction Endonuclease Analysis ◽  
Gene Region ◽  
Beta Globin ◽  
Gamma Delta ◽  
Beta Globin Gene ◽  
Hereditary Persistence

We report restriction endonuclease analysis of the gamma-delta-beta- globin gene region in a mother and child heterozygous for G gamma-beta +-hereditary persistence of fetal hemoglobin (HPFH). The affected chromosome in these persons directs the production of G gamma-chains and beta-chains but not A gamma-chains. DNA was digested with several restriction enzymes and was examined for gamma, delta, beta sequences by blot hybridization. Only normal digestion fragments were present. By sensitive methods, we were unable to detect a deletion in the entire gamma-delta-beta-globin gene region of the affected chromosome, indicating that in this family, G gamma-beta +-HPFH is not due to a large deletion.

Eastern European (delta beta) zero-thalassemia: molecular characterization of a novel 9.1-kb deletion resulting in high levels of fetal hemoglobin in the adult [see comments]

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3738-3745
Author(s):  
A Palena ◽  
A Blau ◽  
G Stamatoyannopoulos ◽  
NP Anagnou
Keyword(s):  
Globin Gene ◽  
Adult Life ◽  
Fetal Hemoglobin ◽  
Direct Repeat ◽  
Regulatory Elements ◽  
Negative Control ◽  
Beta Thalassemia ◽  
Eastern European ◽  
Beta Globin ◽  
Beta Globin Gene

Abstract A novel deletion in the human beta-globin gene cluster associated with increased levels of fetal hemoglobin (HbF) in adult life was molecularly characterized in a member of a family of Eastern European descent. The phenotype of the deletion, documented in five members of the family, shows mild hypochromia and microcytosis (mean corpuscular Hb, 24 to 25.9 pg; mean corpuscular volume, 74 to 78.5 fL) but high production of HbF (13% to 24%) with heterocellular distribution (36% to 86% F cells). Extensive restriction enzyme mapping of the beta-globin cluster and sequencing of the region encompassing the breakpoints showed that the deletion starts 1,612 bp upstream of the cap site of the delta-globin gene, and terminates within the first intron of the beta-globin gene, deleting 9.1 kb of DNA. This length is definitely shorter than the average 12.0 kb of the previously characterized (delta beta) zero-thalassemias. The 5′ breakpoint of the new deletion is close to that of the Yugoslavian delta beta-thalassemia deletion, whereas the 3′ breakpoint is very close to those of the Turkish and the Greek beta zero-thalassemia deletions. The breakpoints of the deletion occur within a direct repeat containing a tetranucleotide exhibiting homology to a donor-splice site, and is symmetrically flanked by a set of 13- and 14-bp homologous complementary sequences, respectively. It is likely that the deletion may be the result of an “illegitimate” or “nonhomologous” recombination event to which these two short sequences may have contributed. It is of interest that the novel deletion (9.1 kb) is comparable to the Italian HPFH-5 deletion (12.9 kb), regarding both the size and the position of the breakpoints. However, the HPFH-5 deletion includes sequences flanking the breakpoints that are preserved in the new deletion. Considering the resulting two discrete phenotypes (ie, delta beta-thalassemia v HPFH), it can be hypothesized that the deleted sequences in the Italian HPFH-5 mutation may harbor regulatory elements that exert a negative control on the gamma-globin gene expression.

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