THALASSEMIA INTERMEDIA AND EXTRAMEDULLARY HEMATOPOIESIS ASSOCIATED WITH COMPOUND HETEROZYGOSITY FOR THE 532 BP DELETION OF THE β-GLOBIN GENE AND GENE DELETION HEREDITARY PERSISTENCE OF FETAL HEMOGLOBIN

CONTEXT: We verified molecular alterations in a 72-year-old Brazilian male patient with a clinical course of homozygous beta-thalassemia intermedia, who had undergone splenectomy and was surviving without regular blood transfusions. The blood cell count revealed microcytic and hypochromic anemia (hemoglobin = 6.5 g/dl, mean cell volume = 74 fl, mean cell hemoglobin = 24 pg) and hemoglobin electrophoresis showed fetal hemoglobin = 1.3%, hemoglobin A2 = 6.78% and hemoglobin A = 79.4%. OBJECTIVE: To identify mutations in a patient with the symptoms of beta-thalassemia intermedia. DESIGN: Molecular inquiry into the mutations possibly responsible for the clinical picture described. SETTING: The structural molecular biology and genetic engineering center of the Universidade Estadual de Campinas, Campinas, Brazil. PROCEDURES: DNA extraction was performed on the patient's blood samples. The polymerase chain reaction (PCR) was done using five specific primers that amplified exons and the promoter region of the beta globin gene. The samples were sequenced and then analyzed via computer programs. RESULTS: Two mutations that cause the disease were found: -101 (C > T) and codon 39 (C > T). CONCLUSIONS: This case represents the first description of 101 (C > T) mutation in a Brazilian population and it is associated with a benign clinical course.

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Expression of the Affected Aγ Globin Gene Associated with Greek Nondeletion Hereditary Persistence of Fetal Hemoglobin

Molecular and Cellular Biology ◽

10.1128/mcb.7.10.3862-3862.1987 ◽

1987 ◽

Vol 7 (10) ◽

pp. 3862-3862

Keyword(s):

Globin Gene ◽

Fetal Hemoglobin ◽

Hereditary Persistence

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Hereditary persistence of fetal hemoglobin or (delta beta)o- thalassemia: three types observed in South-Chinese families

Blood ◽

10.1182/blood.v66.6.1430.bloodjournal6661430 ◽

1985 ◽

Vol 66 (6) ◽

pp. 1430-1435

Author(s):

YT Zeng ◽

SZ Huang ◽

B Chen ◽

YC Liang ◽

ZM Chang ◽

...

Keyword(s):

Gene Mapping ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Restriction Enzymes ◽

Large Deletion ◽

Gamma Delta ◽

Chinese Families ◽

Gamma Globin ◽

Hereditary Persistence ◽

Fetal Hemoglobin Level

Hematological and hemoglobin composition data, and results from extensive gene mapping, using a battery of restriction enzymes and probes, have been used to distinguish different types of hereditary persistence of fetal hemoglobin (HPFH) (or delta beta-thal) among three Chinese families from the southern part of China. The first (Family Z) is an A gamma-(delta beta)+-HPFH without a detectable deletion and may be the same as, or similar to, that described by Farquhar et al (Am J Hum Genet 35:611, 1983). The second (Family C) resembles a G gamma(A gamma delta beta)o-thalassemia and is characterized by a large deletion of DNA originating 3′ to the G gamma globin gene and extending beyond sequences recognized by the pRK28 probe. Data from various digests indicate possible differences in the 3c′ end of the deletion when compared with data for some other types of G gamma(A gamma delta beta)o- thalassemia, described by Trent et al (Br J Haematol 57:279, 1984). The third (Family Zh) concerns a G gamma A gamma(delta beta)+-HPFH, which is characterized in heterozygotes by a fetal hemoglobin level of 20% to 25% with a G gamma value averaging 60% and by the absence of any DNA deletion detectable by extensive gene mapping analyses. The C----G mutation at position 202 5c′ to the G gamma globin gene [characteristic for the high G gamma-(delta beta)+-HPFH (Proc Natl Acad Sci USA 81:4894, 1984; Blood 64:1292, 1984)] was absent, but the Xmn I site at position 158 5c′ to the G gamma globin gene [characteristic for a modest increase in G gamma values and thus and increased G gamma to A gamma ratio (Blood)] was present. No indication has yet been obtained explaining the elevation in both G gamma and A gamma chains; haplotyping showed that the chromosome carrying this G gamma A gamma(delta beta)+ determinant is unusual among the Chinese population.

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A novel C→A transversion within the distal CCAAT motif of theGγ-globin gene in the algerianGγβ+-hereditary persistence of fetal hemoglobin

Hemoglobin ◽

10.3109/03630269908996160 ◽

1999 ◽

Vol 23 (2) ◽

pp. 159-169 ◽

Cited By ~ 8

Author(s):

S. Zertal-Zidani ◽

T. Merghoub ◽

R. Ducrocq ◽

N. Gerard ◽

D. Satta ◽

...

Keyword(s):

Globin Gene ◽

Fetal Hemoglobin ◽

Hereditary Persistence

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

Molecular and Cellular Biology ◽

10.1128/mcb.8.2.713 ◽

1988 ◽

Vol 8 (2) ◽

pp. 713-721 ◽

Cited By ~ 22

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.

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The Georgia type of nondeletional hereditary persistence of fetal hemoglobin has a C---T mutation at nucleotide-114 of the A gamma-globin gene [letter]

Blood ◽

10.1182/blood.v77.5.1124.1124 ◽

1991 ◽

Vol 77 (5) ◽

pp. 1124-1125 ◽

Cited By ~ 20

Author(s):

R Oner ◽

F Kutlar ◽

LH Gu ◽

TH Huisman

Keyword(s):

Globin Gene ◽

Fetal Hemoglobin ◽

Gamma Globin ◽

Hereditary Persistence

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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 ◽

10.1182/blood.v64.6.1292.1292 ◽

1984 ◽

Vol 64 (6) ◽

pp. 1292-1296 ◽

Cited By ~ 14

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.

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Screening for trans-acting factors and other factors involved in the activating or silencing of the γ-globin gene during human ontogeny

Biochemistry and Cell Biology ◽

10.1139/o07-007 ◽

2007 ◽

Vol 85 (3) ◽

pp. 347-357

Author(s):

Yan-Ni Ma ◽

Xin Zhang ◽

Jun-Wu Zhang ◽

Xin-Hua Zhang ◽

Rong-Xin Wang

Keyword(s):

Bone Marrow ◽

Differential Expression ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Pcr Analysis ◽

Reverse Transcription Pcr ◽

Genes Encoding ◽

Hereditary Persistence ◽

Differential Display Reverse Transcription ◽

Human Ontogeny

Researchers hope to increase γ-globin expression by controlling potential trans-acting factors that specifically activate the γ-globin gene in fetuses or silence this gene in adults to potentially treat sickle cell disease and β-thalassemias. To characterize genes encoding such factors, we analyzed the differential expression of mRNAs in erythroid induction cultures of CD34+ cells derived from normal adult bone marrow, umbilical cord blood, and bone marrow from a patient with heterocellular hereditary persistence of fetal hemoglobin. Using differential-display – reverse-transcription PCR analysis, we identified a number of genes with differential expression in the above-mentioned cells. The differential expression of some genes was also confirmed by quantitative real-time PCR. Our data provide important clues for identifying and validating trans-activators that activate the γ-globin gene in fetuses, and trans-acting factors involved in silencing the γ-globin gene in adults.

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Expression of the affected A gamma globin gene associated with Greek nondeletion hereditary persistence of fetal hemoglobin.

Molecular and Cellular Biology ◽

10.1128/mcb.7.8.2999 ◽

1987 ◽

Vol 7 (8) ◽

pp. 2999-3003 ◽

Cited By ~ 13

Author(s):

C J Stoeckert ◽

J E Metherall ◽

M Yamakawa ◽

J M Eisenstadt ◽

S M Weissman ◽

...

Keyword(s):

Transcription Initiation ◽

Globin Gene ◽

Fetal Hemoglobin ◽

Mutant Gene ◽

Retroviral Vector ◽

Base Substitution ◽

Gamma Globin ◽

Erythroleukemia Cell ◽

Hereditary Persistence ◽

Globin Gene Expression

The overexpressed A gamma globin gene in the Greek type of nondeletion hereditary persistence of fetal hemoglobin has a unique single-base substitution located at position -117 relative to the site of transcription initiation. This gene and its normal counterpart were transferred into cultured cell lines by using a retroviral vector. The only difference in expression between the transferred normal and mutant gamma genes was observed in the human erythroleukemia cell line KMOE after exposure of the cells to cytosine arabinoside, a condition that resulted in an adult pattern of endogenous globin gene expression by the cells and was associated with increased expression of the mutant gene.

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