scholarly journals Physiological and Aberrant γ-Globin Transcription During Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Gloria Barbarani ◽  
Agata Labedz ◽  
Sarah Stucchi ◽  
Alessia Abbiati ◽  
Antonella E. Ronchi
Keyword(s):  
Molecular Basis ◽  
Normal Development ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Fetal Period ◽  
Cellular Origin ◽  
Globin Chains ◽  
Pathological Conditions ◽  
Hereditary Persistence ◽  
Adult Cells

The expression of the fetal Gγ- and Aγ-globin genes in normal development is confined to the fetal period, where two γ-globin chains assemble with two α-globin chains to form α2γ2 tetramers (HbF). HbF sustains oxygen delivery to tissues until birth, when β-globin replaces γ-globin, leading to the formation of α2β2 tetramers (HbA). However, in different benign and pathological conditions, HbF is expressed in adult cells, as it happens in the hereditary persistence of fetal hemoglobin, in anemias and in some leukemias. The molecular basis of γ-globin differential expression in the fetus and of its inappropriate activation in adult cells is largely unknown, although in recent years, a few transcription factors involved in this process have been identified. The recent discovery that fetal cells can persist to adulthood and contribute to disease raises the possibility that postnatal γ-globin expression could, in some cases, represent the signature of the fetal cellular origin.

Effective erythropoiesis and HbF reactivation induced by kit ligand in β-thalassemia

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 421-429 ◽  
Author(s):  
Marco Gabbianelli ◽  
Ornella Morsilli ◽  
Adriana Massa ◽  
Luca Pasquini ◽  
Paolo Cianciulli ◽  
...  
Keyword(s):  
Fetal Hemoglobin ◽  
Thalassemia Major ◽  
Globin Genes ◽  
Erythroid Progenitors ◽  
Ineffective Erythropoiesis ◽  
Kit Ligand ◽  
Globin Chains ◽  
In Vitro Response ◽  
Globin Synthesis

In human β-thalassemia, the imbalance between α- and non–α-globin chains causes ineffective erythropoiesis, hemolysis, and anemia: this condition is effectively treated by an enhanced level of fetal hemoglobin (HbF). In spite of extensive studies on pharmacologic induction of HbF synthesis, clinical trials based on HbF reactivation in β-thalassemia produced inconsistent results. Here, we investigated the in vitro response of β-thalassemic erythroid progenitors to kit ligand (KL) in terms of HbF reactivation, stimulation of effective erythropoiesis, and inhibition of apoptosis. In unilineage erythroid cultures of 20 patients with intermedia or major β-thalassemia, addition of KL, alone or combined with dexamethasone (Dex), remarkably stimulated cell proliferation (3-4 logs more than control cultures), while decreasing the percentage of apoptotic and dyserythropoietic cells (<5%). More important, in both thalassemic groups, addition of KL or KL plus Dex induced a marked increase of γ-globin synthesis, thus reaching HbF levels 3-fold higher than in con-trol cultures (eg, from 27% to 75% or 81%, respectively, in β-thalassemia major). These studies indicate that in β-thalassemia, KL, alone or combined with Dex, induces an expansion of effective erythropoiesis and the reactivation of γ-globin genes up to fetal levels and may hence be considered as a potential therapeutic agent for this disease.

scholarly journals A fetal globin gene mutation in A gamma nondeletion hereditary persistence of fetal hemoglobin increases promoter strength in a nonerythroid cell.

1988 ◽  
Vol 8 (2) ◽  
pp. 713-721 ◽  
Author(s):  
M W Rixon ◽  
R E Gelinas
Keyword(s):  
Transient Expression ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Type A ◽  
Base Substitution ◽  
Globin Genes ◽  
Wild Type ◽  
Gamma Globin ◽  
Base Substitutions ◽  
Hereditary Persistence

Single base substitutions have been identified in the promoter regions of A gamma-globin genes from individuals with certain types of nondeletion A gamma hereditary persistence of fetal hemoglobin (HPFH). The presence of these mutations is closely associated with the A gamma HPFH phenotype, but proof that they are the nondeletion HPFH determinants is lacking. To test directly whether these base substitutions can result in an increase in A gamma-globin gene transcription, we studied cosmid clones containing the G gamma- through beta-globin gene regions from individuals with Greek-type (G-to-A base substitution at -117) and Chinese-type (C-to-T base substitution at -196) A gamma HPFH in a transient expression assay. When tested as part of a cosmid clone, the Greek HPFH A gamma-globin gene consistently produced about 1.4 times as much RNA as the wild-type A gamma-globin gene when standardized against RNA transcribed from the G gamma genes in cis. The relative strengths of the normal and HPFH A gamma-globin gene promoters were also compared in transient expression assays with plasmids containing the A gamma-globin genes. Pseudo-wild-type A gamma-globin genes containing a short, transcriptionally neutral deletion were used so that two A gamma-globin genes that differed in their promoter sequences could be compared in the same transfection. The plasmid transient expression results indicated a 1.3- to 1.4-fold increase in steady-state RNA levels from the Greek-type A gamma HPFH promoter compared with the wild-type A gamma promoter, while no difference was documented between the Chinese-type A gamma HPFH promoter and the wild-type A gamma promoter.

scholarly journals Concordance of a point mutation 5' to the G gamma globin gene with G gamma beta +. Hereditary persistence of fetal hemoglobin in the black population

Blood ◽  
1984 ◽  
Vol 64 (6) ◽  
pp. 1292-1296 ◽  
Author(s):  
FS Collins ◽  
CD Boehm ◽  
PG Waber ◽  
CJ Jr Stoeckert ◽  
SM Weissman ◽  
...  
Keyword(s):  
Point Mutation ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Black Population ◽  
Globin Genes ◽  
Beta Globin ◽  
Restriction Endonuclease Site ◽  
Benign Condition ◽  
The Third ◽  
Hereditary Persistence

Abstract Hereditary persistence of fetal hemoglobin (HPFH) is a genetically heterogeneous and clinically benign condition characterized by persistent expression of fetal hemoglobin (Hb F) into adulthood. In the G gamma beta + type, no major deletions in the globin gene cluster occur; adult heterozygotes produce approximately 20% Hb F, which results from overproduction of G gamma chains, with no apparent increase in production from the adjacent A gamma gene. We have recently described a point mutation 202 base pairs 5′ to the cap site of the G gamma gene in an individual with G gamma beta + HPFH. This mutation abolishes a normal ApaI restriction endonuclease site, and thus can be detected by blotting of genomic DNA. We present here further data on the ApaI mutation: (1) It occurs in six of seven families with G gamma beta + HPFH. (2) In three families, detailed haplotype analysis using 11 polymorphic restriction sites in the beta globin cluster has been done. The two that carry the missing ApaI site are identical but the third, which has a normal ApaI pattern, differs from the other two in at least two sites, one of which is a new polymorphic Nco I site between the delta and beta globin genes. This suggests the possibility of a different HPFH mutation in the third family. (3) The haplotype of the G gamma beta + HPFH chromosome carrying the ApaI mutation is different from that of 108 beta A chromosomes of black individuals that have been tested. (4) The G gamma ApaI site is normal in 61 beta A and 109 beta S alleles from non-HPFH black individuals, including 22 who share the same haplotype for the intragenic G gamma, A gamma HindIII polymorphisms. These data add support to the possibility that the -202 mutation is actually causative of the G gamma beta + HPFH phenotype.

Absence of messenger RNA and gene DNA for β-globin chains in hereditary persistence of fetal hemoglobin

Cell ◽  
1976 ◽  
Vol 7 (3) ◽  
pp. 323-329 ◽  
Author(s):  
B.G. Forget ◽  
D.G. Hillman ◽  
H. Lazarus ◽  
E.F. Barell ◽  
E.J. Benz ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Fetal Hemoglobin ◽  
Globin Chains ◽  
Hereditary Persistence

scholarly journals β-Hemoglobinopathies: The Test Bench for Genome Editing-Based Therapeutic Strategies

2020 ◽  
Vol 2 ◽  
Author(s):  
Gloria Barbarani ◽  
Agata Łabedz ◽  
Antonella Ellena Ronchi
Keyword(s):  
Genome Editing ◽  
Test Bench ◽  
Fetal Hemoglobin ◽  
Therapeutic Interventions ◽  
Globin Genes ◽  
Inherited Disorders ◽  
Hematopoietic Stem ◽  
Hereditary Persistence ◽  
Adult Hemoglobin ◽  
Α Subunits

Hemoglobin is a tetrameric protein composed of two α and two β chains, each containing a heme group that reversibly binds oxygen. The composition of hemoglobin changes during development in order to fulfill the need of the growing organism, stably maintaining a balanced production of α-like and β-like chains in a 1:1 ratio. Adult hemoglobin (HbA) is composed of two α and two β subunits (α2β2 tetramer), whereas fetal hemoglobin (HbF) is composed of two γ and two α subunits (α2γ2 tetramer). Qualitative or quantitative defects in β-globin production cause two of the most common monogenic-inherited disorders: β-thalassemia and sickle cell disease. The high frequency of these diseases and the relative accessibility of hematopoietic stem cells make them an ideal candidate for therapeutic interventions based on genome editing. These strategies move in two directions: the correction of the disease-causing mutation and the reactivation of the expression of HbF in adult cells, in the attempt to recreate the effect of hereditary persistence of fetal hemoglobin (HPFH) natural mutations, which mitigate the severity of β-hemoglobinopathies. Both lines of research rely on the knowledge gained so far on the regulatory mechanisms controlling the differential expression of globin genes during development.

scholarly journals Sardinian G gamma-HPFH: a T----C substitution in a conserved "octamer" sequence in the G gamma-globin promoter

Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 815-817 ◽  
Author(s):  
S Ottolenghi ◽  
S Nicolis ◽  
R Taramelli ◽  
N Malgaretti ◽  
R Mantovani ◽  
...  
Keyword(s):  
Globin Gene ◽  
Single Point ◽  
Point Mutations ◽  
Fetal Hemoglobin ◽  
Regulatory Elements ◽  
Globin Genes ◽  
Gamma Globin ◽  
New Type ◽  
Hereditary Persistence ◽  
Globin Promoter

Abstract A survey of hemoglobinopathies in Northern Sardinia allowed the identification of two subjects heterozygous for a new type of G gamma hereditary persistence of fetal hemoglobin (HPFH). The G gamma-globin gene from the HPFH chromosome shows the presence of a T----C substitution 175 nucleotides upstream of the CAP site, adding a new example of single-point mutations occurring in the promoter region of the gamma-globin genes and linked to HPFH phenotypes. In this case the mutation affects the 3′ end nucleotide of a conserved octamer sequence known to be present in other regulatory elements of several genes.

scholarly journals The -158 (C-->T) promoter mutation is responsible for the increased transcription of the 3' gamma gene in the Atlanta type of hereditary persistence of fetal hemoglobin

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3350-3355 ◽  
Author(s):  
DG Efremov ◽  
AJ Dimovski ◽  
TH Huisman
Keyword(s):  
Polymerase Chain Reaction ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Rt Pcr ◽  
Promoter Mutation ◽  
Chain Reaction ◽  
Gamma Globin ◽  
Mapping Analysis ◽  
Hereditary Persistence ◽  
Polymerase Chain

Abstract The Atlanta type of hereditary persistence of fetal hemoglobin (HPFH) is characterized by a mild elevation of Hb F (2% to 5% in heterozygotes), almost exclusively of the G gamma type (more than 90%). Gene-mapping analysis has identified this condition as a -G gamma-G gamma- arrangement with the -158 (C-->T) substitution in the promoters of both G gamma genes. We have reevaluated this condition in members of two families. Sequence analysis identified only two changes in the 3′ gamma gene as compared with the A gamma gene from a chromosome with haplotype no. 3 (or Senegal), namely the -158 (C-->T) promoter mutation and the C-->G change in codon (CD) 136, which accounts for the -G gamma- G gamma- phenotype. The absence of any other nucleotide (nt) substitution provides genetic evidence that the -158 (C-->T) change is primarily responsible for the elevated Hb F levels associated with this condition. A quantitative reverse transcription/polymerase chain reaction (RT/PCR) procedure, presented in detail in this report, was developed to determine the effect of this mutation on the transcription of individual gamma genes in four individuals with the Atlanta type of HPFH. Both gamma-globin genes, ie, the (5′) G gamma and the (3′) G gamma-Atlanta genes of the Atlanta type of HPFH chromosome, expressed elevated amounts of transcripts, which were present in nearly equal amounts. This shows that the -158 (C-->T) mutation exerts its effect on the transcriptional rate of the gene with which it is associated.

scholarly journals Sequence analysis of the gamma-globin gene locus from a patient with the deletion form of hereditary persistence of fetal hemoglobin

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 499-504 ◽  
Author(s):  
CA Stolle ◽  
LA Penny ◽  
S Ivory ◽  
BG Forget ◽  
EJ Jr Benz
Keyword(s):  
Allelic Variation ◽  
Polymerase Chain Reaction Amplification ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Chromosomal Dna ◽  
Gamma Globin ◽  
Allele Specific ◽  
Reaction Amplification ◽  
Hereditary Persistence

Abstract The gamma-globin genes from a patient homozygous for a deletion form of hereditary persistence of fetal hemoglobin (HPFH-1) have been cloned and sequenced. The DNA sequence of the patient's gamma-globin genes corresponds to a previously identified sequence framework (chromosome A) with the exception of 10 base changes. Seven of these base changes can be attributed to normal allelic variation generated by small gene conversion events. The remaining three base changes are present in a 0.76 kb HindIII fragment containing a putative enhancer located 3′ to the A gamma-globin gene. The same three base changes have also been described in the Seattle variant of nondeletion HPFH. We have analyzed 16 alleles from non-HPFH individuals and five alleles from individuals with nondeletion or deletion HPFH for the presence of these base changes by polymerase chain reaction amplification of cloned or chromosomal DNA and hybridization to allele-specific oligonucleotide probes. Although these base changes were found in an individual with HPFH-2, they were not found in the DNA from two patients with nondeletion HPFH. More importantly, all three base changes were detected in DNA from five non-HPFH individuals and appear to be common in blacks. We conclude that these base changes do not correlate with an HPFH phenotype and that the significant mutation in HPFH-1 is the deletion of over 100 kb of genomic DNA.

scholarly journals Expression of Human Globin Genes in Transgenic Mice Carrying the ?-Globin Gene Cluster with a Mutation CausingG??+Hereditary Persistence of Fetal Hemoglobin

1990 ◽  
Vol 612 (1 Sixth Cooley') ◽  
pp. 167-178 ◽  
Author(s):  
MINORU TANAKA ◽  
JUDITH A. NOLAN ◽  
AJAY K. BHARGAVA ◽  
KIRSTEN ROOD ◽  
FRANCIS S. COLLINS ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Gene Cluster ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Globin Gene Cluster ◽  
Hereditary Persistence

scholarly journals Thalassemias and Other Hemoglobinopathies in Former Yugoslavia

2008 ◽  
Vol 11 (1) ◽  
pp. 11-26
Author(s):  
G Efremov
Keyword(s):  
Molecular Basis ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Former Yugoslavia ◽  
Molecular Defect ◽  
Molecular Analyses ◽  
Hereditary Persistence ◽  
Β Chain ◽  
Codon Mutation ◽  
New Mutations

Thalassemias and Other Hemoglobinopathies in Former YugoslaviaThis review summarizes our results on the epidemiology and molecular basis of thalassemias and other hemoglobinopathies in the republics and provinces of the Former Yugoslavia. Over the past 40 years, surveys of more than 37,000 school children and more than 1,600 adults, from all over Former Yugoslavia, except Slovenia, have shown an average incidence of β-thalassemia (β-thal) trait of 1.2%, ranging from 2.9% in the south (Macedonia) to 0.8% in the northwest (Croatia). The frequency of δβ-thal was 0.2%, while that of Swiss type hereditary persistence of fetal hemoglobin (HPFH) was 0.4%. Screening of 12,680 newborns has shown that the frequency of α-thal trait was 1.5%. The molecular basis of the thalassemias in the populations of Former Yugoslavia has been completely defined. More than 700 β-thal chromosomes have been studied and their molecular defect was determined. In the Macedonian population, 16 different β-thal mutations were detected, four of which (IVS-I-110, G→A; IVS-I-6, T>C; IVS-I-1, G>A and codon 39, C>T) accounted for 85% of all β-thal chromosomes. In the Croatian population, 18 different β-thal alleles were detected. Four new mutations [nucleotide (nt) -87, C>A; IVS-II-850, G>C; initiation codon mutation T>C; polyadenylation signal (poly A), AATAAA>AATGAA)] and one new deletion (1605 bp), were characterized. Molecular analyses of DNA from over 50 unrelated cases with δβ-thal have shown that this condition was mainly caused by a 13 kb deletion (Sicilian type); in one family, a deletion of >18 to 23 kb (Macedonian-Turkish type), and in another, a deletion of 148 kb (Yugoslavian type of εγδβ-thal) of the β-globin gene complex, were discovered. Molecular analyses of α-thal from Former Yugoslavia revealed the following defects: the -20.5, -17.5 and -3.7 kb deletions, a 5 nt deletion, and Hb Icaria [α142, Term→Lys (TAA>TCA in α2)]. The incidence of abnormal hemoglobins (Hbs) in Former Yugoslavia was 0.3%. Five different α chain variants in 16 families, 16 different β chain variants in 61 families, one δ chain variant in one family, two types of Hb Lepore in 122 families and two γ chain variants, have been characterized.

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