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

Blood ◽  
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.

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

Blood ◽  
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

Abstract 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.

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.

scholarly journals The breakpoint of a large deletion causing hereditary persistence of fetal hemoglobin occurs within an erythroid DNA domain remote from the beta-globin gene cluster

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2178-2186
Author(s):  
EA Feingold ◽  
BG Forget
Keyword(s):  
Globin Gene ◽  
Adult Life ◽  
Fetal Hemoglobin ◽  
Large Deletion ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Erythroid Cells ◽  
Enhancer Element ◽  
Gamma Globin ◽  
Hereditary Persistence

The DNA juxtaposed to the gamma-globin genes as a result of a large deletion associated with hereditary persistence of fetal hemoglobin (HPFH) was studied to define the role it may play in maintaining active expression of these genes in adult erythroid cells. The DNA located immediately 3′ to the deletion breakpoint was found to function as an enhancer element in gene transfer experiments and to be specifically hypomethylated in normal erythroid cells of both fetal and adult origin. This DNA also contains a long open reading frame encoding a polypeptide chain 292 amino acids in length. Therefore, in this form of HPFH (HPFH-1), the continued expression of gamma-globin genes in adult life may result from the inclusion of these genes within a new chromosomal domain that is potentially transcriptionally active in adult erythroid cells. The 3′ breakpoint of another large deletion causing delta beta thalassemia rather than HPFH was also identified. This deletion (Spanish G gamma A gamma (delta beta) degrees thalassemia) is nearly identical in size and location to that of HPFH- 1, but extends an additional 8.5 to 9 kb in the 3′direction, and therefore results in loss of the sequences near the 3′ breakpoint of HPFH-1. Thus, the presence of these sequences appears to be important for the expression of the HPFH phenotype.

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

Abstract 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.

scholarly journals The breakpoint of a large deletion causing hereditary persistence of fetal hemoglobin occurs within an erythroid DNA domain remote from the beta-globin gene cluster

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2178-2186 ◽  
Author(s):  
EA Feingold ◽  
BG Forget
Keyword(s):  
Globin Gene ◽  
Adult Life ◽  
Fetal Hemoglobin ◽  
Large Deletion ◽  
Beta Thalassemia ◽  
Globin Genes ◽  
Erythroid Cells ◽  
Enhancer Element ◽  
Gamma Globin ◽  
Hereditary Persistence

Abstract The DNA juxtaposed to the gamma-globin genes as a result of a large deletion associated with hereditary persistence of fetal hemoglobin (HPFH) was studied to define the role it may play in maintaining active expression of these genes in adult erythroid cells. The DNA located immediately 3′ to the deletion breakpoint was found to function as an enhancer element in gene transfer experiments and to be specifically hypomethylated in normal erythroid cells of both fetal and adult origin. This DNA also contains a long open reading frame encoding a polypeptide chain 292 amino acids in length. Therefore, in this form of HPFH (HPFH-1), the continued expression of gamma-globin genes in adult life may result from the inclusion of these genes within a new chromosomal domain that is potentially transcriptionally active in adult erythroid cells. The 3′ breakpoint of another large deletion causing delta beta thalassemia rather than HPFH was also identified. This deletion (Spanish G gamma A gamma (delta beta) degrees thalassemia) is nearly identical in size and location to that of HPFH- 1, but extends an additional 8.5 to 9 kb in the 3′direction, and therefore results in loss of the sequences near the 3′ breakpoint of HPFH-1. Thus, the presence of these sequences appears to be important for the expression of the HPFH phenotype.

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

1987 ◽  
Vol 7 (8) ◽  
pp. 2999-3003 ◽  
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.

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 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.

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