scholarly journals Laotian (delta beta) degree-thalassemia: molecular characterization of a novel deletion associated with increased production of fetal hemoglobin

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 983-988 ◽  
Author(s):  
JW Zhang ◽  
G Stamatoyannopoulos ◽  
NP Anagnou
Keyword(s):  
Globin Gene ◽  
Repetitive Sequences ◽  
Adult Life ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Mild Anemia ◽  
F Cells

Abstract We have identified and molecularly characterized a novel deletion in the beta-globin gene cluster that increases fetal hemoglobin (HbF) synthesis in a 24-year-old Laotian man who is heterozygous for this mutation. The patient is asymptomatic with a mild anemia, hypochromia, and microcytosis (Ht = 39%, MCH = 22.8 pg, MCV = 71 fl), normal levels of HbA2 (3.0%) and 11.5% HbF (G gamma A gamma ratio 60 to 40), with heterocellular distribution (52% F cells). Extensive restriction endonuclease mapping defined the 5′ breakpoint within the IVS II of the delta-globin gene, between positions 775 to 781 very similar to the 5′ breakpoint of the Sicilian delta beta-thalassemia. However, the 3′ breakpoint was localized between two Pst I sites 4.7 kb 3′ of the beta- globin gene, thus ending about 0.7 kb upstream from the 3′ breakpoint of the Sicilian delta beta-thalassemia. This results in a 12.5 kb deletion of DNA. It is of interest that the 5′ breakpoint of the deletion residues within an AT-rich region which has been proposed as a specific recognition signal for recombination events, while the 3′ breakpoint lies within a cluster of L1 repetitive sequences (formerly known as Kpn I family repeats). The presence of the 3′ breakpoints of several other deletions within this region of L1 repeats also suggests that such sequences might serve as hot spots for recombination and eventually lead to thalassemia deletions. The similarity of the 5′ and 3′ breakpoints of these delta beta-thalassemias underscores the putative regulatory role of the deleted and juxtaposed sequences on the expression of the gamma-globin genes in adult life.

scholarly journals Laotian (delta beta) degree-thalassemia: molecular characterization of a novel deletion associated with increased production of fetal hemoglobin

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 983-988 ◽  
Author(s):  
JW Zhang ◽  
G Stamatoyannopoulos ◽  
NP Anagnou
Keyword(s):  
Globin Gene ◽  
Repetitive Sequences ◽  
Adult Life ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Beta Globin ◽  
Beta Globin Gene ◽  
Mild Anemia ◽  
F Cells

We have identified and molecularly characterized a novel deletion in the beta-globin gene cluster that increases fetal hemoglobin (HbF) synthesis in a 24-year-old Laotian man who is heterozygous for this mutation. The patient is asymptomatic with a mild anemia, hypochromia, and microcytosis (Ht = 39%, MCH = 22.8 pg, MCV = 71 fl), normal levels of HbA2 (3.0%) and 11.5% HbF (G gamma A gamma ratio 60 to 40), with heterocellular distribution (52% F cells). Extensive restriction endonuclease mapping defined the 5′ breakpoint within the IVS II of the delta-globin gene, between positions 775 to 781 very similar to the 5′ breakpoint of the Sicilian delta beta-thalassemia. However, the 3′ breakpoint was localized between two Pst I sites 4.7 kb 3′ of the beta- globin gene, thus ending about 0.7 kb upstream from the 3′ breakpoint of the Sicilian delta beta-thalassemia. This results in a 12.5 kb deletion of DNA. It is of interest that the 5′ breakpoint of the deletion residues within an AT-rich region which has been proposed as a specific recognition signal for recombination events, while the 3′ breakpoint lies within a cluster of L1 repetitive sequences (formerly known as Kpn I family repeats). The presence of the 3′ breakpoints of several other deletions within this region of L1 repeats also suggests that such sequences might serve as hot spots for recombination and eventually lead to thalassemia deletions. The similarity of the 5′ and 3′ breakpoints of these delta beta-thalassemias underscores the putative regulatory role of the deleted and juxtaposed sequences on the expression of the gamma-globin genes in adult life.

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.

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.

scholarly journals Fetal hemoglobin silencing in humans

Blood ◽  
2006 ◽  
Vol 108 (6) ◽  
pp. 2081-2086 ◽  
Author(s):  
Patricia A. Oneal ◽  
Nicole M. Gantt ◽  
Joseph D. Schwartz ◽  
Natarajan V. Bhanu ◽  
Y. Terry Lee ◽  
...  
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Beta Thalassemia ◽  
Postnatal Life ◽  
Globin Genes ◽  
Beta Globin ◽  
Globin Mrna ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Age Related

Abstract Interruption of the normal fetal-to-adult transition of hemoglobin expression should largely ameliorate sickle cell and beta-thalassemia syndromes. Achievement of this clinical goal requires a robust understanding of gamma-globin gene and protein silencing during human development. For this purpose, age-related changes in globin phenotypes of circulating human erythroid cells were examined from 5 umbilical cords, 99 infants, and 5 adult donors. Unexpectedly, an average of 95% of the cord blood erythrocytes and reticulocytes expressed HbA and the adult beta-globin gene, as well as HbF and the gamma-globin genes. The distribution of hemoglobin and globin gene expression then changed abruptly due to the expansion of cells lacking HbF or gamma-globin mRNA (silenced cells). In adult reticulocytes, less than 5% expressed gamma-globin mRNA. These data are consistent with a “switching” model in humans that initially results largely from gamma- and beta-globin gene coexpression and competition during fetal development. In contrast, early postnatal life is marked by the rapid accumulation of cells that possess undetectable gamma-globin mRNA and HbF. The silencing phenomenon is mediated by a mechanism of cellular replacement. This novel silencing pattern may be important for the development of HbF-enhancing therapies.

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 Molecular characterization of a novel form of (A gamma delta beta)zero thalassemia deletion in a Chinese family

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1624-1629
Author(s):  
JW Zhang ◽  
WF Song ◽  
YJ Zhao ◽  
GY Wu ◽  
ZM Qiu ◽  
...  
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Chinese Family ◽  
Globin Genes ◽  
Beta Globin ◽  
Gamma Delta ◽  
Enhancer Element ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Mild Anemia

We have identified and molecularly characterized a novel deletion in the beta-globin gene cluster that is associated with elevated fetal hemoglobin in the adult. The propositus is a homozygote from the Yunnan province of China. The deletion spans about 90 kb of DNA and removes the A gamma, delta, and beta-globin genes. The 5' breakpoint of the deletion is located about 0.13 kb upstream from the A gamma-globin gene, whereas the 3' breakpoint is located about 66 kb downstream from the beta-globin gene, about 13 kb upstream from the breakpoint of the Chinese (A gamma delta beta)zero-thalassemia. Heterozygotes for this Yunnanese form of (A gamma delta beta)zero-thalassemia express between 9% and 17% of fetal hemoglobin, whereas the homozygote present with a mild anemia (Hb = 10.7 g/dl). Comparison of the sites of 3' breakpoints of the Yunnanese and the Chinese (A gamma delta beta)zero-thalassemia mutants is compatible with the hypothesis that an enhancer element is located between the 3' breakpoints of these two mutants. Juxta-position to the G gamma gene of this element may be responsible for the efficient gamma-gene expression in the Yunnanese mutant.

scholarly journals Molecular characterization of a novel form of (A gamma delta beta)zero thalassemia deletion in a Chinese family

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1624-1629 ◽  
Author(s):  
JW Zhang ◽  
WF Song ◽  
YJ Zhao ◽  
GY Wu ◽  
ZM Qiu ◽  
...  
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Chinese Family ◽  
Globin Genes ◽  
Beta Globin ◽  
Gamma Delta ◽  
Enhancer Element ◽  
Beta Globin Gene ◽  
Gamma Globin ◽  
Mild Anemia

Abstract We have identified and molecularly characterized a novel deletion in the beta-globin gene cluster that is associated with elevated fetal hemoglobin in the adult. The propositus is a homozygote from the Yunnan province of China. The deletion spans about 90 kb of DNA and removes the A gamma, delta, and beta-globin genes. The 5' breakpoint of the deletion is located about 0.13 kb upstream from the A gamma-globin gene, whereas the 3' breakpoint is located about 66 kb downstream from the beta-globin gene, about 13 kb upstream from the breakpoint of the Chinese (A gamma delta beta)zero-thalassemia. Heterozygotes for this Yunnanese form of (A gamma delta beta)zero-thalassemia express between 9% and 17% of fetal hemoglobin, whereas the homozygote present with a mild anemia (Hb = 10.7 g/dl). Comparison of the sites of 3' breakpoints of the Yunnanese and the Chinese (A gamma delta beta)zero-thalassemia mutants is compatible with the hypothesis that an enhancer element is located between the 3' breakpoints of these two mutants. Juxta-position to the G gamma gene of this element may be responsible for the efficient gamma-gene expression in the Yunnanese mutant.

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