Gene Structure in Hereditary Persistence of Fetal Hemoglobin Individuals

Gel blot hybridization studies on DNA from individuals heterozygous for different types of hereditary persistence of fetal hemoglobin (HPFH) have shown a good correlation in gene structures with those deduced from data obtained in studies of the hemoglobins found in members of the families. The recent data have also shown that in certain individuals additional strong hybridizing bands are present. The origin of these bands is as present unresolved, but it may be that they represent additional genes.     

Molecular Mechanism of High Hemoglobin F Production in Southeast Asian-Type Hereditary Persistence of Fetal Hemoglobin

Hereditary persistence of fetal hemoglobin (HPFH) is associated with a high level of hemoglobin F (HbF) synthesis in adult heterozygotes. In this study, 2 of 6 unrelated HPFH Thai families were found to be Southeast Asian-type HPFH (SEA-HPFH) by analyses of the hematologic data and Southern blot hybridization with polymerase chain reaction-amplified DNA probes. DNA mapping with a probe for a delta-globin fragment showed a 27-kb deletion of DNA that included the beta-globin gene and the 3' deoxyribonuclease I hypersensitive site 1 (3'HS1) sequence downstream. Deletion of the insulator, 3'HS1, and the juxta-position of the HPFH-3 core enhancer downstream to the 3' breakpoint have been postulated to be the cause of high HbF production in these individuals. To test this hypothesis, we transfected K562 cells with 4 different bacterial artificial chromosome constructs containing the enhanced green fluorescent protein (EGFP) gene at the position of the Agamma-globin gene (pEBAC/148beta:EGFP). Flow cytometry was used to compare EGFP expression from the pEBAC/148beta:EGFP construct with the HPFH-3 core enhancer immediately 5' to the SEA-HPFH breakpoint (pEnH), from the pEBAC/148beta:EGFP construct with 8 kb of the breakpoint sequence and the HPFH-3 core enhancer (pSEA-HPFH), and from the construct with 3'HS1 followed by the pSEA-HPFH sequence (pSEA-HPFH_3pHS1). The results show that high HbF production in SEA-HPFH occurs from a deletion of the 3'HS1 sequence and the juxtaposition of the HPFH-3 enhancer downstream to the delta-globin gene.     

Hereditary Persistence of Fetal Hemoglobin in Greece. A Study and a Comparison

The features of hereditary persistence of fetal hemoglobin in six Greekfamilies are described. In eight cases this abnormality was associated withtypical -thalassemia; in all these cases Hb A was the major hemoglobin component. The clinical and hematologic picture was that of mild thalassemia. Thefindings are compared to relevant observations in cases of Negro origin andseveral differences are stressed. It is tentatively concluded that the inheritedabnormality occurring in these families is responsible for an incompleteshift from the fetal to the adult type of hemoglobinopoiesis, i.e., from synthesis of -chains to the production of -and -chains.

Submitted on October 17, 1963 Accepted on January 24, 1964     

Molecular Characterization of Hereditary Persistence of Fetal Hemoglobin in the Karen People of Thailand

Hereditary persistence of fetal hemoglobin (HPFH) is the condition whereby a continuously active γ‐globin gene expression leads to elevated fetal hemoglobin (Hb F) levels in adult life [Stamatoyannopoulos G, Grosveld F. Hemoglobin switching. In: Stamatoyannopoulos G, Majerus PW, Perlmutter RM, Varmus H, eds. The Molecular Basis of Blood Diseases. Philadelphia: W.B. Saunders, 2001:135–182; Wood WG. Hereditary persistence of fetal hemoglobin and δβ thalassemia. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge: Cambridge University Press, 2001:356–388; and Weatherall DJ, Clegg JB. Hereditary persistence of fetal hemoglobin. In: Weatherall DJ, Clegg JB, eds. The Thalassaemia Syndromes. Oxford: Blackwell Scientific Publishers, 1981:450–507]. The condition is caused either by mutation of the β‐ and γ‐globin genes, or the γ‐gene controlled region on other chromosomes. Several families with this condition have been reported from Vietnam, Cambodia and China, and the Southeast Asian mutation (or HPFH‐6), a 27 kb deletion, was demonstrated. Here we report on a mother and her daughter of the Karen ethnic group with high levels of Hb F, living in the Suan Pueng District on the border of Thailand and Myanmar. Genotyping showed a heterozygosity for the 27 kb deletion of the β‐globin gene. Their conditions have been confirmed by gap polymerase chain reaction (PCR) with three oligonucleotide primers recently developed by Xu et al. [Xu X‐M, Li Z‐Q, Liu Z‐Y, Zhong X‐L, Zhao Y‐Z, Mo Q‐H. Molecular characterization and PCR detection of a deletional HPFH: application to rapid prenatal diagnosis for compound heterozygotes of this defect with β‐thalassemia in a Chinese family. Am J Hematol 2000; 65:183–188.], and a DNA sequencing method. Thus far there has been no official report of the HPFH‐6 anomaly from Thailand. The compound heterozygosity of β‐thalassemia (thal) and hereditary persistence of Hb F causes the phenotype of thalassemia intermedia; in contrast, homozygotes for this anomaly show only mild microcytic anemia. Hence, genetic counseling for hereditary persistence of Hb F carriers is needed for family planning.     

Genetics of Hb F/F Cell Variance in Adults and Heterocellular Hereditary Persistence of Fetal Hemoglobin

Hb F and F cell values in normal adults vary considerably with a continuous distribution that is substantially skewed to the right implicating a polygenic influence. The high values of Hb F and F cells are transmitted in the condition referred to as heterocellular hereditary persistence fetal hemoglobin which should be regarded as a multifactorial quantitative trait, quite distinct from the classical pancellular hereditary persistence of fetal hemoglobins. Several factors have been shown to influence F cell/Hb F levels in normal adults including age, gender, genetic determinants linked and unlinked to the β-globin locus on chromosome 11p. Two trans-acting quantitative trait loci for F cell variance have been mapped, one on 6q and the other on Xp, with at least one other implicated. As an initial step towards hunting for the other quantitative trait loci we have carried out a preliminary analysis of F cell variance in 182 pairs of monozygotic and 373 pairs of dizygotic twins. The correlation coefficient of F cell variance in monozygotic twins was 0.89, while that in the dizygotic twins was 0.51. Overwhelming evidence for a strong genetic component in the control of Hb F/F cell levels is provided by a heritability of 0.87. However, the role and extent of contribution from the quantitative trait loci on 6q and Xp are still not known.     

Hereditary Persistence of Fetal Hemoglobin: A Study of 79 Affected Persons in 15 Negro Families in Baltimore

Hereditary persistence of fetal hemoglobin is an anomaly of hemoglobinproduction apparently caused by a mutant gene that inhibits synthesis ofhemoglobins A and A₂. Alkali-resistant hemoglobin indistinguishable fromhemoglobin F of umbilical cord blood is produced, presumably as a compensatory phenomenon, so that neither anemia nor hypochromia of the red cellsoccurs. The data summarized are compatible with the hypothesis that functionof the loci of the and chains of globin is wholly suppressed, quite possibly by a mutant "operator" gene affecting linked structural loci. Heterozygotesfor the anomaly have high concentrations of hemoglobin F in the erythrocytes,with a remarkably uniform distribution of fetal hemoglobin throughout thered cell population. Erythrocytes of persons with the anomaly resembleadult red cells with respect to the non-hemoglobin proteins and the oxygendissociation curve. Experience with 79 affected Negroes in Baltimore is compared with that reported by other investigators. The occasional difficulty indifferentiating the anomaly from other conditions, particularly thalassemia,is emphasized.

Submitted on July 23, 1962     

Hereditary Persistence of Fetal Hemoglobin Caused by Single Nucleotide Promoter Mutations in Sickle Cell Trait and Hb SC Disease

Hereditary persistence of fetal hemoglobin (HPFH) can be caused by point mutations in the γ-globin gene promoters. We report three rare cases: a child compound heterozygous for Hb S (HBB: c.20A?>?T) and HPFH with a novel point mutation in the ^Aγ-globin gene promoter who had 42.0% Hb S, 17.0% Hb A and 38.0% Hb F; a man with Hb SC (HBB: c.19G?>?A) disease and a point mutation in the ^Gγ-globin gene promoter who had 54.0% Hb S, 18.0% Hb C and 25.0% Hb F; a child heterozygous for Hb S and HPFH due to mutations in both the ^Aγ- and ^Gγ-globin gene promoters in cis [^Gγ^Aγ(β⁺) HPFH], with 67.0% Hb A, 6.5% Hb S and 25.0% Hb F.     

Variations in Globin Chain Synthesis in Hereditary Persistence of Fetal Haemoglobin

Globin synthesis was studied in four Negro families including 10 members with Hb A-HPFH and four with Hb S-HPFH. The beta/alpha specific activity ratios in 10 of these HPFH heterozygotes were similar to those of the control group. In two patients with Hb A-HPFH, the beta/alpha ratio was slightly decreased in one (0.84) and clearly decreased in another (0.78). In two of the patients with Hb S-HPFH the ratios were clearly decreased (0.71 and 0.75). The extended range of beta/alpha ratios in these 14 patients is similar to that of Negro patients with beta-thalassaemia trait. These studies indicate that a decreased beta/alpha ratio may be found in HPFH, as well as in beta-thalassaemia. Bone marrow globin synthesis was measured in two patients with Hb S-HPFH and decreased peripheral blood beta/alpha ratios, and in one with Hb A-HPFH and a normal peripheral blood beta/alpha ratio. In each patient the (beta+gamma)/alpha ratio of radioactivities as well as the beta/alpha specific activity ratio was close to 1 and therefore balanced, indicating more rapid decay of beta-chain synthesis relative to alpha-chain during red cell maturation or extremely rapid destruction of newly synthesized excess alpha-chains in the bone marrow.     

Hereditary Spherocytosis with High Fetal Hemoglobin: An Interesting Case

Raised Hb F is occasionally found in stress erythropoiesis associated with hemolytic anemias. In hereditary spherocytosis (HS), elevation of Hb F by 2–5% may be seen but Hb F in the range of 10–20% has not been reported. We present an interesting case of a child, initially presenting with high Hb F, who showed a spontaneous and progressive decline, and was subsequently diagnosed to have HS with raised fetal hemoglobin (Hb F) using an eosin-5-maleimide flow cytometric test.     

The Natural History of Hb S/Hereditary Persistence of Fetal Hemoglobin in 13 Children from the State of Minas Gerais,Brazil

Children with Hb S (HBB: c.20A?>?T)/hereditary persistence of fetal hemoglobin (Hb S/HPFH) have a mild clinical phenotype, but some complications have been reported. The natural history of Hb S/HPFH in children from the State of Minas Gerais, Brazil newborn cohort is described. Clinical and hematological data regarding participants’ phenotypes were retrieved from medical records. The HPFH-1, HPFH-2, and HPFH-3 and α-thalassemia (α-thal) deletions were detected by gap-polymerase chain reaction (gap-PCR). Thirteen children were included, nine (69.2%) had the Hb S/HPFH-2 deletion, and four (30.8%) had Hb S/HPFH-1 deletion; 11 children (84.6%) had αα/αα, and two (15.4%) carried the αα/?α^3.7 (rightward) deletion. The mean concentration of total hemoglobin (Hb) and Hb F was 12.52?±?0.56?g/dL and 42.31%?±?1.97%, respectively. Mild microcytosis and hypochromia were observed. We found acute clinical manifestations of sickle cell disease, such as acute chest syndrome (ACS) and acute pain crisis in four children; nine (69.2%) children were completely asymptomatic during the follow-up period. All children were classified as having low-risk transcranial Doppler (TDC). In conclusion, children with Hb S/HPFH have a mild clinical phenotype of sickle cell disease, although acute clinical manifestations may occur. High Hb F levels and absence of anemia are common hematological characteristics.     

Interaction between Homozygous β0 Thalassaemia and the Swiss Type of Hereditary Persistence of Fetal Haemoglobin

The interaction between β⁰ thalassaemia and an heterocellular form of hereditary persistence of fetal haemoglobin (HPFH), presumably of the Swiss type, has been studied in three generations of a family in which both traits occur. The haematological parameters and the segregation of the two characters in the family suggest that the propositus, a 52-year-old male from southern Sardinia, is homozygous for β⁰ thalassaemia and carrier of the HPFH.
In spite of the complete suppression of adult haemoglobin synthesis, the patient is not anaemic and shows only morphological abnormalities of the red cells associated with a moderate decrease of the erythrocyte life span. Studies of the synthesis of haemoglobin chains in vitro have revealed only a mild degree of unbalance in the propositus, with a γ/α ratio of 0–67, and a very slight unbalance in a 3-year-old child heterozygous for β thalassaemia and HPFH.
Preliminary analysis of the linkage between this kind of heterocellular HPFH and the β Hb locus has been performed, utilizing all the suitable families reported in the literature. Although positive lod scores (1.535) have been obtained at a recombination fraction of 0.20, the data available are not sufficient to conclude in favour or against the linkage between the β Hb locus and the heterocellular type of HPFH.     

A Plea for the Newborn Diagnosis of Hb S-Hereditary Persistence of Fetal Hemoglobin

The gene for hereditary persistence of fetal hemoglobin (HPFH) in the Caribbean is much more common than previously estimated. To avoid labeling persons with the benign syndrome Hb S (HBB: c.20A>T)/HPFH as a disease and wasting scarce resources, parental studies are recommended when newborn screening reveals a pattern consistent with an SS phenotype.     

Hereditary Persistence of Foetal Haemogloblll in a Thai Family: The First Instance in the Mongol Race and in Association with Haemoglobin E

S ummary . Hereditary persistence of foetal haemoglobin is described in a Thai family. The AF heterozygotes were healthy and had normal haematological findings except the decrease in haemoglobin A₂ level and the presence of a large amount of haemoglobin F. The latter, comprising 21–22 per cent, is higher than in the Greek but lower than in the Negro counterparts. Three persons, who were heterozygous for both haemoglobin E and high F genes, were not anaemic but had numerous target-erythrocytes; haemoglobin E constituted 40 per cent, the rest being haemoglobin F. Acid-elution staining revealed haemoglobin F in every red cell in both AF and EF heterozygotes. The absence of haemoglobin A in the latter suggests allelism between this type of hereditary persistence of foetal haemoglobin and haemoglobin E or β-structural gene.     

Two Novel Mutations (HBG1: c.-250C>T and HBG2: c.-250C>T) Associated With Hereditary Persistence of Fetal Hemoglobin

Mutations within the promoters of either of the γ-globin genes [^Gγ (HBG1) and ^Aγ (HBG2)] lead to variably increased levels of fetal hemoglobin (Hb) (Hb F, α2γ2) in the syndrome of hereditary persistence of fetal Hb (HPFH). Carriers of such mutations are clinically asymptomatic and the mutations are usually detected as part of routine screening or family studies. We describe two new nondeletional HPFH mutations, both C>T substitutions at position c.-250, one in the HBG1 and the other in the HBG2 globin gene promoters.     

The Negro Variety of Hereditary Persistence of Fetal Haemoglobin is a Mild Form of Thalassaemia

S ummary . Further studies have been carried out on blood of the 15-year-old Negro male from Baltimore who was the first reported case of the homozygous state for hereditary persistence of fetal haemoglobin. His red cells contain only Hb F; Hbs A and A₂ have never been detected. Over a 15-year period of follow up the red cells of this individual have shown persistent microcytosis with reduced MCH and MCV values. His whole-blood p50 value is decreased, probably because of lack of interaction between Hb F and 2,3-diphosphoglycerate. However, his haemoglobin level at the age of 15 years is lower than would be predicted from the degree of increased oxygen affinity. Globin-chain synthesis studies suggest that this is because he has a mild thalassaemia disorder with an α/γ-chain production ratio of about 1.5, similar to that found in β-thalassaemia heterozygotes. Thus Negro HPFH appears to be a well-compensated form of δβ thalassaemia.     

A Japanese Family with Two Sisters Apparently Homozygous for Mk

Two Japanese sisters with consanguineous parents have M-N- En(a-) Wr(a-b-) S-s-U- red cells and are therefore apparently homozygous for Mk; the third reported family with members of this genotype. The serum of the proposita (ORCMK) contained anti-EnaTS, anti-EnaFR and possibly anti-Wrb, whereas the serum of her MkMk sister contained no atypical antibodies. Total absence of sialoglycoproteins alpha and delta from red cell membranes of an Mk homozygote was demonstrated by lactoperoxidase-catalysed radioiodination of accessible tyrosine residues with subsequent SDS polyacrylamide gel electrophoresis and autoradiography, and by use of a monoclonal antibody directed at the cytoplasmic portion of alpha-sialoglycoprotein.     

Carbonic Anhydrase and Fetal Hemoglobin in Thyrotoxicosis

An adult patient with thyrotoxicosis had erythrocyte carbonic anhydrasedeficiency and an abnormally high level of fetal hemoglobin. After treatmentof the hyperthyroidism, the erythrocyte carbonic anhydrase level became normaland the level of Hb F dropped. Twelve other patients with hyperthyroidismand not related to this index case were studied. Most of them were alreadyunder treatment. Nine had erythrocyte carbonic anhydrase deficiency; two hadan increase of fetal hemoglobin. The possible relationship of increase of fetalhemoglobin, erythrocyte carbonic anhydrase deficiency and thyrotoxicosis isdiscussed.

Submitted on March 1, 1967 Accepted on April 7, 1967