scholarly journals Thalassemias and Other Hemoglobinopathies in Former Yugoslavia

2008 ◽  
Vol 11 (1) ◽  
pp. 11-26
Author(s):  
G Efremov

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.

Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1430-1435
Author(s):  
YT Zeng ◽  
SZ Huang ◽  
B Chen ◽  
YC Liang ◽  
ZM Chang ◽  
...  

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.


Hemoglobin ◽  
1999 ◽  
Vol 23 (2) ◽  
pp. 159-169 ◽  
Author(s):  
S. Zertal-Zidani ◽  
T. Merghoub ◽  
R. Ducrocq ◽  
N. Gerard ◽  
D. Satta ◽  
...  

1988 ◽  
Vol 8 (2) ◽  
pp. 713-721 ◽  
Author(s):  
M W Rixon ◽  
R E Gelinas

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.


Blood ◽  
1984 ◽  
Vol 64 (6) ◽  
pp. 1292-1296 ◽  
Author(s):  
FS Collins ◽  
CD Boehm ◽  
PG Waber ◽  
CJ Jr Stoeckert ◽  
SM Weissman ◽  
...  

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.


2007 ◽  
Vol 85 (3) ◽  
pp. 347-357
Author(s):  
Yan-Ni Ma ◽  
Xin Zhang ◽  
Jun-Wu Zhang ◽  
Xin-Hua Zhang ◽  
Rong-Xin Wang

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.


1987 ◽  
Vol 7 (8) ◽  
pp. 2999-3003 ◽  
Author(s):  
C J Stoeckert ◽  
J E Metherall ◽  
M Yamakawa ◽  
J M Eisenstadt ◽  
S M Weissman ◽  
...  

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.


Blood ◽  
1988 ◽  
Vol 71 (3) ◽  
pp. 815-817 ◽  
Author(s):  
S Ottolenghi ◽  
S Nicolis ◽  
R Taramelli ◽  
N Malgaretti ◽  
R Mantovani ◽  
...  

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.


Blood ◽  
1985 ◽  
Vol 66 (6) ◽  
pp. 1430-1435 ◽  
Author(s):  
YT Zeng ◽  
SZ Huang ◽  
B Chen ◽  
YC Liang ◽  
ZM Chang ◽  
...  

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.


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