scholarly journals Fetal hemoglobin-containing cells have the same mean corpuscular hemoglobin as cells without fetal hemoglobin: a reciprocal relationship between gamma- and beta-globin gene expression in normal subjects and in those with high fetal hemoglobin production

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1109-1113 ◽  
Author(s):  
GJ Dover ◽  
SH Boyer
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Reciprocal Relationship ◽  
Transmitted Light ◽  
Red Cells ◽  
Mean Corpuscular Hemoglobin ◽  
Beta Globin ◽  
Corpuscular Hemoglobin ◽  
Normal Individuals ◽  
F Cells

Abstract We have developed methodology that allows comparison of the mean corpuscular hemoglobin (MCH) of fetal hemoglobin (HbF)-containing red cells (F cells) with the MCH of non-F cells from the same individual. To do this, suspensions of peripheral blood erythrocytes and their internal contents are fixed with an imidodiester, dimethyl-3,3′- dithiobispropionimidate dihydrochloride (DTBP). Thereafter fixed cells are made permeable to antisera by treatment with Triton X-100 and isopropanol, reacted with a mouse monoclonal antibody (MoAb) against HbF, and then with fluorescein-conjugated antimouse IgG. No appreciable hemoglobin is lost during such manipulation. Red cells from a diversity of subjects were thus treated and examined microscopically, first by transmitted light and then by epifluorescence. A direct correlation between Coulter-derived MCH and mean absorbance of 415 nm transmitted light was found for 100 unfixed (r = 0.96) and for 100 antibody-treated fixed-permeabilized red cells (r = 0.99) among individuals selected so as to provide a range of Coulter MCH values between 20 and 35. Comparisons of microscopically derived MCH of F cells and non-F cells were statistically nondistinguishable (P greater than 0.05) in all subjects. Such comparisons included normal individuals (less than 1% F cells), SS patients (7% to 48% F cells), subjects with congenital anemia (22% to 65% F cells), individuals with heterocellular hereditary persistence of HbF (HPFH) (12% to 21% F cells), and heterozygotes for beta + thalassemia (11% to 31% F cells). We conclude that gamma- and beta-globin production within F cells is regulated in a reciprocal fashion both among normal individuals and among individuals with elevated HbF production.

scholarly journals Fetal hemoglobin-containing cells have the same mean corpuscular hemoglobin as cells without fetal hemoglobin: a reciprocal relationship between gamma- and beta-globin gene expression in normal subjects and in those with high fetal hemoglobin production

Blood ◽  
1987 ◽  
Vol 69 (4) ◽  
pp. 1109-1113 ◽  
Author(s):  
GJ Dover ◽  
SH Boyer
Keyword(s):  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Reciprocal Relationship ◽  
Transmitted Light ◽  
Red Cells ◽  
Mean Corpuscular Hemoglobin ◽  
Beta Globin ◽  
Corpuscular Hemoglobin ◽  
Normal Individuals ◽  
F Cells

We have developed methodology that allows comparison of the mean corpuscular hemoglobin (MCH) of fetal hemoglobin (HbF)-containing red cells (F cells) with the MCH of non-F cells from the same individual. To do this, suspensions of peripheral blood erythrocytes and their internal contents are fixed with an imidodiester, dimethyl-3,3′- dithiobispropionimidate dihydrochloride (DTBP). Thereafter fixed cells are made permeable to antisera by treatment with Triton X-100 and isopropanol, reacted with a mouse monoclonal antibody (MoAb) against HbF, and then with fluorescein-conjugated antimouse IgG. No appreciable hemoglobin is lost during such manipulation. Red cells from a diversity of subjects were thus treated and examined microscopically, first by transmitted light and then by epifluorescence. A direct correlation between Coulter-derived MCH and mean absorbance of 415 nm transmitted light was found for 100 unfixed (r = 0.96) and for 100 antibody-treated fixed-permeabilized red cells (r = 0.99) among individuals selected so as to provide a range of Coulter MCH values between 20 and 35. Comparisons of microscopically derived MCH of F cells and non-F cells were statistically nondistinguishable (P greater than 0.05) in all subjects. Such comparisons included normal individuals (less than 1% F cells), SS patients (7% to 48% F cells), subjects with congenital anemia (22% to 65% F cells), individuals with heterocellular hereditary persistence of HbF (HPFH) (12% to 21% F cells), and heterozygotes for beta + thalassemia (11% to 31% F cells). We conclude that gamma- and beta-globin production within F cells is regulated in a reciprocal fashion both among normal individuals and among individuals with elevated HbF production.

scholarly journals An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, beta-globin haplotypes, alpha-globin gene number, gender, and age

Blood ◽  
1995 ◽  
Vol 85 (4) ◽  
pp. 1111-1117 ◽  
Author(s):  
YC Chang ◽  
KD Smith ◽  
RD Moore ◽  
GR Serjeant ◽  
GJ Dover
Keyword(s):  
Sickle Cell ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Beta Globin ◽  
Gene Number ◽  
Cohort Group ◽  
Five Factors ◽  
F Cells ◽  
Alpha Globin

Five factors have been shown to influence the 20-fold variation of fetal hemoglobin (Hb F) levels in sickle cell anemia (SS): age, sex, the alpha-globin gene number, beta-globin haplotypes, and an X-linked locus that regulates the production of Hb F-containing erythrocytes (F cells), ie, the F-cell production (FCP) locus. To determine the relative importance of these factors, we studied 257 Jamaican SS subjects from a Cohort group identified by newborn screening and from a Sib Pair study. Linear regression analyses showed that each variable, when analyzed alone, had a significant association with Hb F levels (P < .05). Multiple regression analysis, including all variables, showed that the FCP locus is the strongest predictor, accounting for 40% of Hb F variation. beta-Globin haplotypes, alpha-globin genes, and age accounted for less than 10% of the variation. The association between the beta-globin haplotypes and Hb F levels becomes apparent if the influence of the FCP locus is removed by analyzing only individuals with the same FCP phenotype. Thus, the FCP locus is the most important factor identified to date in determining Hb F levels. The variation within each FCP phenotype is modulated by factors associated with the three common beta-globin haplotypes and other as yet unidentified factor(s).

scholarly journals Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2

Blood ◽  
1992 ◽  
Vol 80 (3) ◽  
pp. 816-824 ◽  
Author(s):  
GJ Dover ◽  
KD Smith ◽  
YC Chang ◽  
S Purvis ◽  
A Mays ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Beta Globin ◽  
Chromosome 11 ◽  
Cell Production ◽  
Flow Cytometric ◽  
Normal Individuals ◽  
Restriction Sites ◽  
F Cells ◽  
Polymorphic Restriction

Abstract Fetal hemoglobin (Hb F) production in sickle cell (SS) disease and in normal individuals varies over a 20-fold range and is under genetic control. Previous studies suggested that variant Hb F levels might be controlled by genetic loci separate from the beta-globin complex on chromosome 11. Using microscopic radial immunodiffusion and flow cytometric immunofluorescent assays to determine the percentage of F reticulocytes and F cells in SS and nonanemic individuals, we observed that F-cell levels were significantly higher in nonanemic females than males (mean +/- SD, 3.8% +/- 3.2% v 2.7% +/- 2.3%). F-cell production as determined by F reticulocyte levels in SS females was also higher than in SS males (17% +/- 10% v 13% +/- 8%). We tested the hypothesis that F-cell production in both normal and anemic SS individuals was controlled by an X-linked locus with two alleles, high (H) and low (L). Using an algorithm to determine the 99.8% confidence interval of a normal distribution in nonanemic individuals, we estimated that males and females with at least one H allele had greater than 3.3% F cells. Comparisons of male-male or female-female SS sib pairs with discordant F reticulocyte levels distinguished two phenotypes in SS males (L, less than 12%; H, greater than 12%) and three phenotypes in SS females (LL, less than 12%; HL, 12% to 24%, HH greater than 24%). Linkage analysis using polymorphic restriction sites along the X chromosome in eight SS and one AA family localized the F-cell production (FCP) locus to Xp22.2, with a maximum lod score (logarithm of odds of linkage v independent assortment) of 4.6 at a recombination fraction of 0.04.

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.

Two Distinct Genetic Mechanisms Modify the Level of HbA2 in Peripheral Blood,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3193-3193
Author(s):  
Swee Lay Thein ◽  
Chad P. Garner ◽  
Tim D Spector ◽  
Stephan Menzel
Keyword(s):  
Gene Expression ◽  
Peripheral Blood ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Nucleotide Polymorphisms ◽  
Beta Globin ◽  
Erythroid Progenitors ◽  
Genome Wide ◽  
F Cells

Abstract Abstract 3193 The switch from embryonic to fetal hemoglobin (HbF, α2γ2) in utero, and from fetal to adult hemoglobin at birth is well documented and achieved by the sequential activation of ε, γ and δ/β genes at the β globin gene (HBB) cluster. A change in the expression of hemoglobin genes also take place in adult erythropoiesis: earlier erythroid progenitors have been shown to produce significant amounts of fetal hemoglobin, while the more mature progenitors contain essentially none. In keeping with the sequential activation of β-like globin genes, δ globin chain synthesis also declines as maturation in erythroid progenitors progresses. Understanding the developmental changes of gene expression at the beta globin locus is not purely of academic interest, since a therapeutic induction of HbF or HbA2 (α2δ2) production would be of significant clinical benefit for patients with a defect of HbA (α2β2) function or abundance, such as sickle cell disease or β thalassemia. We have previously studied the genetic regulation of fetal hemoglobin persistence in a genome-wide association study (GWAS) in healthy volunteers, and are now extending this approach to the study of HbA2. Our study population is the 'Twins UK' twin registry of healthy Europeans, mostly female adult individuals, with genome-wide single polymorphisms (SNP) data and hemoglobin phenotypes for a primary study group (n=2,340) and a second replication group (n=1,880). A quantitative trait GWAS analysis was carried out to assess the relationship between SNPs and the HbA2 trait. We found that HbA2 (as a percentage of total hemoglobin) was weakly, but significantly, correlated with the amount of fetal hemoglobin carrying cells (F cells) an individual possesses (r = 0.14, p < 0.01). This suggests the existence of some common biological process that influences both hemoglobin species. We also found that the same SNP alleles at chromosome 6q23.3 (HBS1L-MYB, peak signal rs7775698, p = 2.51×10−9) that are associated with a boost in the prevalence of F cells and larger red blood cells (denoted by the mean cell volume or MCV) also promote HbA2 levels, again pointing to some common biological factor connected with the erythropoietic maturation process. Interestingly, neither of the other two major HbF loci, BCL11A on chromosome 2p, or the HbF-promoting regions within the HBB cluster (at the β LCR and the γ globin genes) on chromosome 11p, showed association with HbA2 levels. Instead, SNPs around the β globin gene itself (clearly separate also from the delta gene) exert a significant influence on HbA2 levels (peak association rs12793110, p=5.11×10−12) (see Figure 1). In contrast to the HBS1L-MYB region on chromosome 6, the HbA2-boosting alleles at these SNPs do not increase red blood cell MCV. We propose that the SNPs around HBB influences HbA2 (ie. δ globin gene) expression via a mechanism that is related to the competitive process between the β and δ gene expression that might mimic a very mild β thalassemic effect. Figure 1: Association with single-nucleotide polymorphisms (SNP) near the beta globin gene cluster on chromosome 11p15.4 with abundance of HbA2 (filled circles ¥) and F cells (empty circles ○) in the peripheral blood of Northern European adults (Twins UK). Figure 1:. Association with single-nucleotide polymorphisms (SNP) near the beta globin gene cluster on chromosome 11p15.4 with abundance of HbA2 (filled circles ¥) and F cells (empty circles ○) in the peripheral blood of Northern European adults (Twins UK). We propose that the systematic genetic study of specialized hematological traits in healthy volunteers can help to understand the biology of hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

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 Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2

Blood ◽  
1992 ◽  
Vol 80 (3) ◽  
pp. 816-824 ◽  
Author(s):  
GJ Dover ◽  
KD Smith ◽  
YC Chang ◽  
S Purvis ◽  
A Mays ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Fetal Hemoglobin ◽  
Beta Globin ◽  
Chromosome 11 ◽  
Cell Production ◽  
Flow Cytometric ◽  
Normal Individuals ◽  
Restriction Sites ◽  
F Cells ◽  
Polymorphic Restriction

Fetal hemoglobin (Hb F) production in sickle cell (SS) disease and in normal individuals varies over a 20-fold range and is under genetic control. Previous studies suggested that variant Hb F levels might be controlled by genetic loci separate from the beta-globin complex on chromosome 11. Using microscopic radial immunodiffusion and flow cytometric immunofluorescent assays to determine the percentage of F reticulocytes and F cells in SS and nonanemic individuals, we observed that F-cell levels were significantly higher in nonanemic females than males (mean +/- SD, 3.8% +/- 3.2% v 2.7% +/- 2.3%). F-cell production as determined by F reticulocyte levels in SS females was also higher than in SS males (17% +/- 10% v 13% +/- 8%). We tested the hypothesis that F-cell production in both normal and anemic SS individuals was controlled by an X-linked locus with two alleles, high (H) and low (L). Using an algorithm to determine the 99.8% confidence interval of a normal distribution in nonanemic individuals, we estimated that males and females with at least one H allele had greater than 3.3% F cells. Comparisons of male-male or female-female SS sib pairs with discordant F reticulocyte levels distinguished two phenotypes in SS males (L, less than 12%; H, greater than 12%) and three phenotypes in SS females (LL, less than 12%; HL, 12% to 24%, HH greater than 24%). Linkage analysis using polymorphic restriction sites along the X chromosome in eight SS and one AA family localized the F-cell production (FCP) locus to Xp22.2, with a maximum lod score (logarithm of odds of linkage v independent assortment) of 4.6 at a recombination fraction of 0.04.

scholarly journals beta-thalassemia intermedia in a Brazilian patient with - 101(C > T) and codon 39 (C > T) mutations

2003 ◽  
Vol 121 (1) ◽  
pp. 28-30
Author(s):  
Sylvia Morais de Sousa ◽  
Letícia Khater ◽  
Luís Antônio Peroni ◽  
Karine Miranda ◽  
Marcelo Jun Murai ◽  
...  
Keyword(s):  
Clinical Course ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Hypochromic Anemia ◽  
Beta Thalassemia ◽  
Beta Globin ◽  
Thalassemia Intermedia ◽  
Mean Cell Volume ◽  
Molecular Alterations ◽  
Brazilian Patient

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.

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 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.

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