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Gene Review

HBFQTL2  -  hereditary persistence of fetal hemoglobin...

Homo sapiens

Synonyms: FCP, HPFH
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Disease relevance of HPFH

  • Recently, a trans-acting locus controlling Hb F and FC production has been mapped to chromosome 6q23 in an Asian Indian kindred that includes individuals with heterocellular hereditary persistence of Hb F (HPFH) associated with beta thalassemia [1].
  • We have tested this hypothesis for an element that covers the minimal distance between the thalassemia and HPFH deletions and is thought to be responsible for the difference between a deletion HPFH and deltabeta-thalassemia, located 5' of the delta-globin gene [2].
  • Three proteins present in nuclear extracts of erythroleukemia cells bind to this CCAAT region and contact the nucleotide mutated in Greek HPFH [3].
  • Fragments of the non-alpha-globin cluster from two patients were cloned in cosmid and phage lambda vectors, and assigned to either the HPFH or beta-thalassemic chromosome on the basis of the demonstration of a polymorphic BglII site in the HPFH gamma-globin cluster [4].
  • It is speculated that a subclass (the G gamma-(G gamma A gamma)-beta+ HPFH) in which beta S chains are produced in cis to HPFH in conjunction with true beta S genes in trans may be responsible for "mild" cases of sickle cell anemia [5].

High impact information on HPFH

  • A similar result was obtained using DNA prepared from cultured skin fibroblasts from an individual homozygous for the Negro form of hereditary persistence of fetal hemoglobin (HPFH) [6].
  • To test whether the point mutation found in the Greek non-deletion HPFH (guanine to adenine at nucleotide position -117) is the cause of the raised gamma-globin levels in the adult stage and is not just a linked polymorphism, we engineered this mutation into a gamma-globin gene [7].
  • In hereditary persistence of fetal haemoglobin (HPFH), inappropriately high gamma-globin expression in adult life is associated with deletions in the beta-globin cluster or with single-base changes upstream of the gamma-globin genes [8].
  • We observe that a single change (at -175, T----C) found in HPFH leads to increased promoter activity only in erythroid cells [8].
  • To account for enhanced gamma-gene expression in HPFH of the non-deletion type, we tested the nuclear proteins of human erythroleukaemia cells that bind gamma-promoter sequences in vitro by correlating specific mutations in their binding sites with promoter activity [8].

Biological context of HPFH

  • However, a point mutation (-198 T----C) associated with hereditary persistence of fetal hemoglobin (HPFH) dramatically increased the affinity of this site for Sp1 and significantly increased Sp1 dependent promoter strength in SL-2 cells [9].
  • Thus, our observations provide support for a model whereby HPFH conditions arise from the juxtaposition of enhancers as well as permissive chromatin subdomains in the vicinity of the gamma-globin genes [10].
  • Greek HPFH is a non-deletion variety in which heterozygotes produce 10-20% HbF, predominantly due to overproduction of the A gamma chain [11].
  • The findings raise the possibility that the phenotype of HPFH is not simply the direct result of mutations in or around globin genes but the consequence of the mutations on the interaction of globin genes with trans-acting regulatory factors [12].
  • However, most cases of HPFH and delta 0-beta 0-thalassaemia are associated with extensive deletions in the globin gene cluster [13].

Anatomical context of HPFH

  • In the G gamma beta+ type of HPFH, erythrocytes of adult heterozygotes contain approximately equal to 20% Hb F, which is almost exclusively of the G gamma-globin variety, without increased levels of gamma-globin chains from the nearby A gamma-globin gene [14].
  • The HPFH/beta o-thal patient produced 100% gamma in reticulocytes and in colonies [15].
  • Since the beta-promoter constructs were poorly expressed in fetal cells, new plasmids containing an HPFH promoter (Ggamma(-175), T to C), which is strongly expressed in both fetal and adult cell lines, were made [16].
  • Three gamma-globin promoters containing mutations associated with hereditary persistence of fetal hemoglobin (HPFH), -202 C----G, -196 C----T and -117 G----A, were not overexpressed in K562 cells, consistent with the hypothesis that these promoters are not overexpressed in fetal erythroblasts, only in adult red cells [17].
  • We have introduced into the mouse germ line the 40-kilobase (kb) Kpn I fragment containing the beta-globin gene cluster from an individual with a non-deletion form of hereditary persistence of fetal hemoglobin (HPFH) believed to be due to a point mutation at position -202 of the G gamma-globin gene [18].

Associations of HPFH with chemical compounds

  • Amounts of beta-N-terminal glycohemoglobins (HbX1c), serum fructosamine, and erythrocyte polyamines were determined in nondiabetic adults with HbAA, HbAC, HbAS, HbCC, HbSC, HbSS, and HbS/hereditary persistent HbF (HPFH) [19].
  • Haemoglobin F has been isolated from the red cells of individuals with the Greek form of hereditary persistence of fetal haemoglobin (HPFH), and the glycine/alanine composition of the gamma CB3 peptides determined [20].

Physical interactions of HPFH


Enzymatic interactions of HPFH

  • In a patient homozygous for the G gamma A gamma type of HPFH at least 24 kb of DNA in the globin gene region has been deleted to remove most of the gamma-delta intergenic region and the delta and beta globin genes [22].

Regulatory relationships of HPFH

  • The mice carrying the -117 A gamma G-->A mutation displayed a delayed gamma- to beta-globin gene switch and continued to express A gamma-globin chains in the adult stage of development as expected for carriers of Greek HPFH, indicating that the YAC/transgenic mouse system allows the analysis of the developmental role of cis-acting motifs [23].

Other interactions of HPFH

  • Deletions at the 3' end of the human beta-globin locus are associated with the hereditary persistence of fetal hemoglobin (HPFH) in adults, potentially through the juxtaposition of enhancer elements in the vicinity of the fetal gamma-globin genes [10].
  • A mutation of T to C at position -175 in the gamma-globin promoter GATA site, associated with hereditary persistence of fetal hemoglobin (HPFH), increased expression of these promoters in both fetal and adult cells [24].
  • We have also shown that supercoiled plasmids containing the gamma-228 to -189 region contain a high affinity binding site for BP-8 that is stabilized by factors that stabilize H-DNA; two HPFH point mutations (-202 C-->G or C-->T) that destabilize the secondary DNA structure abolish the high affinity binding site [25].
  • Co-culture of erythroid progenitors from 10 patients with thalassemia major or thalassemia variant (HPFH/thalassemia, sickle/beta 0-thalassemia) with 200 U/ml IFN-gamma also resulted in a significant decrease in picograms and percent of HbF per BFU-E-derived erythroblast [26].
  • To test the hypothesis in a much stricter basis, we produced beta locus YAC transgenic mice carrying an exact beta locus replicate of a deletional HPFH mutation, HPFH 2 [27].

Analytical, diagnostic and therapeutic context of HPFH

  • Molecular cloning and sequence analysis of a nondeletion form of Sicilian beta o hereditary persistence of fetal hemoglobinemia (HPFH) (mutation in IVS2 nt1 position) homozygous for haplotype III revealed the presence of four sequence variations: C----T at -158 5' to G gamma, T----C at +2285, C----A at +2476, and A----G at +2676, all 3' to A gamma [28].
  • Restriction endonuclease mapping of gamma-delta-beta-globin region in G gamma (beta)+ HPFH and a Chinese A gamma HPFH variant [29].
  • DNA at the end point of the gene deletion associated with one form of hereditary persistence of fetal hemoglobin (HPFH) was cloned and used as a probe in gene mapping experiments to analyze the extent and approximate 3' end points of various deletions associated with HPFH and delta beta-thalassemia [30].
  • Using probes from the Spanish (delta beta)zero-thalassemic DNA, the 3' breakpoint region has been mapped to a point approximately 8.5 to 9.0 kb downstream from that of HPFH type 1 and, as we know the restriction sites 3' to this breakpoint, the presence of the deletion can be identified with the polymerase chain reaction (PCR) [31].
  • Sequence analysis of the enhancer region located 3' to the A gamma-globin gene from the putative HPFH chromosome revealed three base substitutions, whereas this region was normal in the A gamma-globin gene linked to the beta A gene [32].


  1. Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23. Garner, C., Mitchell, J., Hatzis, T., Reittie, J., Farrall, M., Thein, S.L. Am. J. Hum. Genet. (1998) [Pubmed]
  2. Deletion of a region that is a candidate for the difference between the deletion forms of hereditary persistence of fetal hemoglobin and deltabeta-thalassemia affects beta- but not gamma-globin gene expression. Calzolari, R., McMorrow, T., Yannoutsos, N., Langeveld, A., Grosveld, F. EMBO J. (1999) [Pubmed]
  3. The -117 mutation in Greek HPFH affects the binding of three nuclear factors to the CCAAT region of the gamma-globin gene. Superti-Furga, G., Barberis, A., Schaffner, G., Busslinger, M. EMBO J. (1988) [Pubmed]
  4. A molecular study of a family with Greek hereditary persistence of fetal hemoglobin and beta-thalassemia. Giglioni, B., Casini, C., Mantovani, R., Merli, S., Comi, P., Ottolenghi, S., Saglio, G., Camaschella, C., Mazza, U. EMBO J. (1984) [Pubmed]
  5. A G gamma type of the hereditary persistence of fetal hemoglobin with beta chain production in cis. Huisman, T.H., Miller, A., Schroeder, W.A. Am. J. Hum. Genet. (1975) [Pubmed]
  6. Delta-beta-thalassemia is due to a gene deletion. Ottolenghi, S., Comi, P., Giglioni, B., Tolstoshev, P., Lanyon, W.G., Mitchell, G.J., Williamson, R., Russo, G., Musumeci, S., Schillro, G., Tsistrakis, G.A., Charache, S., Wood, W.G., Clegg, J.B., Weatherall, D.J. Cell (1976) [Pubmed]
  7. A single point mutation is the cause of the Greek form of hereditary persistence of fetal haemoglobin. Berry, M., Grosveld, F., Dillon, N. Nature (1992) [Pubmed]
  8. Increased gamma-globin expression in a nondeletion HPFH mediated by an erythroid-specific DNA-binding factor. Martin, D.I., Tsai, S.F., Orkin, S.H. Nature (1989) [Pubmed]
  9. Interaction of Sp1 with the human gamma globin promoter: binding and transactivation of normal and mutant promoters. Gumucio, D.L., Rood, K.L., Blanchard-McQuate, K.L., Gray, T.A., Saulino, A., Collins, F.S. Blood (1991) [Pubmed]
  10. Persistent gamma-globin expression in adult transgenic mice is mediated by HPFH-2, HPFH-3, and HPFH-6 breakpoint sequences. Katsantoni, E.Z., Langeveld, A., Wai, A.W., Drabek, D., Grosveld, F., Anagnou, N.P., Strouboulis, J. Blood (2003) [Pubmed]
  11. A point mutation in the A gamma-globin gene promoter in Greek hereditary persistence of fetal haemoglobin. Collins, F.S., Metherall, J.E., Yamakawa, M., Pan, J., Weissman, S.M., Forget, B.G. Nature (1985) [Pubmed]
  12. A haemoglobin switching activity modulates hereditary persistence of fetal haemoglobin. Papayannopoulou, T., Tatsis, B., Kurachi, S., Nakamoto, B., Stamatoyannopoulos, G. Nature (1984) [Pubmed]
  13. The deletion in a type of delta 0-beta 0-thalassaemia begins in an inverted AluI repeat. Ottolenghi, S., Giglioni, B. Nature (1982) [Pubmed]
  14. G gamma beta+ hereditary persistence of fetal hemoglobin: cosmid cloning and identification of a specific mutation 5' to the G gamma gene. Collins, F.S., Stoeckert, C.J., Serjeant, G.R., Forget, B.G., Weissman, S.M. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  15. Fetal hemoglobin synthesis in erythroid cultures in hereditary persistence of fetal hemoglobin and beta o-thalassemia. Weinberg, R.S., Antonarakis, S.E., Kazazian, H.H., Dover, G.J., Orkin, S.H., Lenes, A.L., Schofield, J.M., Alter, B.P. Blood (1984) [Pubmed]
  16. A region upstream of the human delta-globin gene shows a stage-specific interaction with globin promoters in erythroid cell lines. Vitale, M., Calzolari, R., Di Marzo, R., Acuto, S., Maggio, A. Blood Cells Mol. Dis. (2001) [Pubmed]
  17. Function of transfected globin promoters and the globin locus activator in K562 erythroleukemia cells. Ulrich, M.J., Moon, A.M., Ley, T.J. Ann. N. Y. Acad. Sci. (1990) [Pubmed]
  18. Expression of human globin genes in transgenic mice carrying the beta-globin gene cluster with a mutation causing G gamma beta + hereditary persistence of fetal hemoglobin. Tanaka, M., Nolan, J.A., Bhargava, A.K., Rood, K., Collins, F.S., Weissman, S.M., Forget, B.G., Chamberlain, J.W. Ann. N. Y. Acad. Sci. (1990) [Pubmed]
  19. Beta-N-terminal glycohemoglobins in subjects with common hemoglobinopathies: relation with fructosamine and mean erythrocyte age. Martina, W.V., Martijn, E.G., van der Molen, M., Schermer, J.G., Muskiet, F.A. Clin. Chem. (1993) [Pubmed]
  20. Occurrence of G gamma Hb F in Greek HPFH: analysis of heterozygotes and compound heterozygotes with beta thalassaemia. Clegg, J.B., Metaxatou-Mavromati, A., Kattamis, C., Sofroniadou, K., Wood, W.G., Weatherall, D.J. Br. J. Haematol. (1979) [Pubmed]
  21. The deletion of the distal CCAAT box region of the A gamma-globin gene in black HPFH abolishes the binding of the erythroid specific protein NFE3 and of the CCAAT displacement protein. Mantovani, R., Superti-Furga, G., Gilman, J., Ottolenghi, S. Nucleic Acids Res. (1989) [Pubmed]
  22. Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH). Bernards, R., Flavell, R.A. Nucleic Acids Res. (1980) [Pubmed]
  23. Use of yeast artificial chromosomes (YACs) in studies of mammalian development: production of beta-globin locus YAC mice carrying human globin developmental mutants. Peterson, K.R., Li, Q.L., Clegg, C.H., Furukawa, T., Navas, P.A., Norton, E.J., Kimbrough, T.G., Stamatoyannopoulos, G. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  24. Functional erythroid promoters created by interaction of the transcription factor GATA-1 with CACCC and AP-1/NFE-2 elements. Walters, M., Martin, D.I. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  25. A human protein containing a "cold shock" domain binds specifically to H-DNA upstream from the human gamma-globin genes. Horwitz, E.M., Maloney, K.A., Ley, T.J. J. Biol. Chem. (1994) [Pubmed]
  26. Interferon-gamma modulates fetal hemoglobin synthesis in sickle cell anemia and thalassemia. Miller, B.A., Olivieri, N., Hope, S.M., Faller, D.V., Perrine, S.P. J. Interferon Res. (1990) [Pubmed]
  27. Juxtaposition of the HPFH2 enhancer is not sufficient to reactivate the gamma-globin gene in adult erythropoiesis. Xiang, P., Han, H., Barkess, G., Olave, I., Fang, X., Yin, W., Stamatoyannopoulos, G., Li, Q. Hum. Mol. Genet. (2005) [Pubmed]
  28. Nucleotide variations in the 3' A gamma enhancer region are linked to beta-gene cluster haplotypes and are unrelated to fetal hemoglobin expression. Ragusa, A., Lombardo, M., Bouhassira, E., Beldjord, C., Lombardo, T., Nagel, R.L., Labie, D., Krishnamoorthy, R. Am. J. Hum. Genet. (1989) [Pubmed]
  29. Restriction endonuclease mapping of gamma-delta-beta-globin region in G gamma (beta)+ HPFH and a Chinese A gamma HPFH variant. Farquhar, M., Gelinas, R., Tatsis, B., Murray, J., Yagi, M., Mueller, R., Stamatoyannopoulos, G. Am. J. Hum. Genet. (1983) [Pubmed]
  30. Different 3' end points of deletions causing delta beta-thalassemia and hereditary persistence of fetal hemoglobin: implications for the control of gamma-globin gene expression in man. Tuan, D., Feingold, E., Newman, M., Weissman, S.M., Forget, B.G. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  31. Rapid detection of Spanish (delta beta)zero-thalassemia deletion by polymerase chain reaction. Vives-Corrons, J.L., Pujades, M.A., Miguel-García, A., Miguel-Sosa, A., Cambiazzo, S. Blood (1992) [Pubmed]
  32. Gamma gene promoter and enhancer structure in Seattle variant of hereditary persistence of fetal hemoglobin. Gelinas, R.E., Rixon, M., Magis, W., Stamatoyannopoulos, G. Blood (1988) [Pubmed]
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