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16 - The Molecular Basis of β Thalassemia, δβ Thalassemia, and Hereditary Persistence of Fetal Hemoglobin

from SECTION FOUR - THE β THALASSEMIAS

Published online by Cambridge University Press:  03 May 2010

Martin H. Steinberg ,
Bernard G. Forget ,
Douglas R. Higgs  and
David J. Weatherall
By
Swee Lay Thein  and
William G. Wood
Martin H. Steinberg
Affiliation:
Boston University
Bernard G. Forget
Affiliation:
Yale University, Connecticut
Douglas R. Higgs
Affiliation:
MRC Institute of Molecular Medicine, University of Oxford
David J. Weatherall
Affiliation:
Albert Einstein College of Medicine, New York
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Summary

INTRODUCTION

The β thalassemias and related disorders are characterized by a quantitative reduction in the production of β-globin chains of HbA. More than 200 β thalassemia alleles have now been characterized (http://globin.cse.psu.edu) involving mutations affecting any of the steps in the transcription of the β-globin gene, posttranscriptional processing of its pre-mRNA, or the translation of its mRNA into protein. The vast majority of simple β thalassemias are caused by point mutations within the gene or its immediate flanking sequences, although small deletions involving the β gene may also occur. If β-chain production is totally abolished by the mutation it is referred to as β0 thalassemia, whereas reduced output of β-chains (of normal structure) produces β+ thalassemia, with the mildest forms sometimes referred to as β++ or “silent” β thalassemia. These common forms of β thalassemias are inherited as haploinsufficient mendelian recessives.

Some structurally abnormal β-chain variants are also associated with quantitative deficiencies of β-globin chain production and have a phenotype of β thalassemia, in which case they are referred to as “thalassemic hemoglobinopathies,” for example, HbE (β26 Glu→Lys). In others, the β-globin variants are so unstable that they undergo very rapid postsynthetic degradation giving rise to a functional deficiency. These hyperunstable β-chain variants act in a dominant negative fashion, causing a disease phenotype even when present in the heterozygous state, and hence have been referred to as “dominantly inherited β thalassemia.” β Thalassemia mutations that segregate independently of the β-globin cluster have been described in occasional families.

Type
Chapter
Information
Disorders of Hemoglobin
Genetics, Pathophysiology, and Clinical Management
 , pp. 323 - 356
Publisher: Cambridge University Press
Print publication year: 2009

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References

Thein, SL. Is it dominantly inherited β thalassaemia or just a β-chain variant that is highly unstable?Br J Haematol. 1999;107:12–21.CrossRefGoogle ScholarPubMed
Forget, BG. Molecular mechanisms of beta thalassemia. In: Steinberg, MH, Forget, BG, Higgs, DR, Nagel, RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. Cambridge: Cambridge University Press; 2001:252–276.Google Scholar
Thein, SL. Pathophysiology of beta thalassemia – a guide to molecular therapies. Hematology (Am Soc Hematol Educ Program). 2005:31–37.Google ScholarPubMed
Weatherall, DJ, Clegg, JB. The Thalassaemia Syndromes. 4th ed. Oxford: Blackwell Science; 2001.CrossRefGoogle Scholar
Forget, BG. Molecular genetics of the human globin genes. In: Steinberg, MH, Forget, BG, Higgs, DR, Nagel, RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. Cambridge: Cambridge University Press; 2001:117–130.Google Scholar
Thein, SL. Structural variants with a beta-thalassemia phenotype. In: Steinberg, MH, Forget, BG, Higgs, DR, Nagel, RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. Cambridge: Cambridge University Press; 2001:342–355.Google Scholar
Wood, WG. Hereditary persistence of fetal hemoglobin and delta beta 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.Google Scholar
Huisman, THJ, Carver, MFH, Baysal, E. A Syllabus of Thalassemia Mutations. Augusta, GA: The Sickle Cell Anemia Foundation; 1997.Google Scholar
Hardison, R, Riemer, C, Chui, DH, Huisman, TH, Miller, W. Electronic access to sequence alignments, experimental results, and human mutations as an aid to studying globin gene regulation. Genomics. 1998;47(3):429–437.CrossRefGoogle ScholarPubMed
Chen, XW, Mo, QH, Li, Q, Zeng, R, Xu, XM. A novel mutation of −73(A→T) in the CCAAT box of the beta-globin gene identified in a patient with the mild beta-thalassemia intermedia. Ann Hematol. 2007;86(9):653–657.CrossRefGoogle Scholar
Safaya, S, Rieder, RF, Dowling, CE, Kazazian, HHJ, Adams, JG. Homozygous β-thalassemia without anemia. Blood. 1989;73:324–328.Google ScholarPubMed
Huang, S-Z, Wong, C, Antonarakis, SE, Ro-Lein, T, Lo, WHY, Kazazian, HHJ. The same TATA box β-thalassemia mutation in Chinese and U.S. blacks: another example of independent origins of mutation. Hum Genet. 1986;74:162–164.CrossRefGoogle Scholar
Thein, SL. Beta thalassaemia. In: Rodgers, GP, ed. Bailliere's Clinical Haematology, Sickle Cell Disease and Thalassaemia. London: Bailliere Tindall; 1998:91–126.Google Scholar
Gonzalez-Redondo, JH, Stoming, TA, Kutlar, A, et al. A C→T substitution at nt −101 in a conserved DNA sequence of the promoter region of the β-globin gene is associated with “silent” β-thalassemia. Blood. 1989;73:1705–1711.Google Scholar
Maragoudaki, E, Kanavakis, E, Traeger-Synodinos, J, et al. Molecular, haematological and clinical studies of the −101 C→T substitution of the β-globin gene promoter in 25 β-thalassaemia intermedia patients and 45 heterozygotes. Br J Haematol. 1999;107:699–706.CrossRefGoogle Scholar
Wong, C, Dowling, CE, Saiki, RK, Higuchi, RG, Erlich, HA, Kazazian, HHJ. Characterization of β-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987;330:384–386.CrossRefGoogle ScholarPubMed
Ho, PJ, Rochette, J, Fisher, CA, et al. Moderate reduction of β-globin gene transcript by a novel mutation in the 5′ untranslated region: a study of its interaction with other genotypes in two families. Blood. 1996;87:1170–1178.Google ScholarPubMed
Huang, S-C, Benz, EJJ. Posttranscriptional factors influencing the hemoglobin content of the red cells. In: Steinberg, MH, Forget, BG, Higgs, DR, Nagel, RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. Cambridge: Cambridge University Press; 2001:252–276.Google Scholar
Treisman, R, Orkin, SH, Maniatis, T. Specific transcription and RNA splicing defects in five cloned β-thalassaemia genes. Nature. 1983;302:591–596.CrossRefGoogle ScholarPubMed
Camaschella, C, Mazza, U, Roetto, A, et al. Genetic interactions in thalassemia intermedia: analysis of β-mutations, α-genotype, γ-promoters, and β-LCR hypersensitive sites 2 and 4 in Italian patients. Am J Hematol. 1995;48:82–87.CrossRefGoogle ScholarPubMed
Ho, PJ, Hall, GW, Luo, LY, Weatherall, DJ, Thein, SL. Beta thalassaemia intermedia: is it possible to predict phenotype from genotype?Br J Haematol. 1998;100:70–78.CrossRefGoogle ScholarPubMed
Rund, D, Oron-Karni, V, Filon, D, Goldfarb, A, Rachmilewitz, E, Oppenheim, A. Genetic analysis of β-thalassemia intermedia in Israel: diversity of mechanisms and unpredictability of phenotype. Am J Hematol. 1997;54:16–22.3.0.CO;2-7>CrossRefGoogle ScholarPubMed
Spritz, RA, Jagadeeswaran, P, Choudary, PV, et al. Base substitution in an intervening sequence of a β+ thalassemic human globin gene. Proc Natl Acad Sci USA. 1981;78:2455–2459.CrossRefGoogle Scholar
Westaway, D, Williamson, R. An intron nucleotide sequence variant in a cloned β+-thalassemia globin gene. Nucl Acids Res. 1981;9:1777.CrossRefGoogle Scholar
Busslinger, M, Moschanas, N, Flavell, RA. β+ thalassemia: aberrant splicing results from a single point mutation in an intron. Cell. 1981;27:289.CrossRefGoogle Scholar
Fukumaki, Y, Ghosh, PK, Benz, EJ, et al. Abnormally spliced messenger RNA in erythroid cells from patients with β+ thalassemia and monkey cells expressing a cloned β+-thalassemic gene. Cell. 1982;28:585–593.CrossRefGoogle ScholarPubMed
Metherall, JE, Collins, FS, Pan, J, Weissman, SM, Forget, BG. β0-thalassemia caused by a base substitution that creates an alternative splice acceptor site in an intron. EMBO J. 1986; 5:2551–2557.Google Scholar
Ho, PJ, Hall, GW, Watt, S, et al. Unusually severe heterozygous β-thalassemia: evidence for an interacting gene affecting globin translation. Blood. 1998;92:3428–3435.Google ScholarPubMed
Yang, KG, Kutlar, F, George, E, et al. Molecular characterization of β-globin gene mutations in Malay patients with Hb E-β-thalassaemia and thalassaemia major. Br J Haematol. 1989;72:73–80.CrossRefGoogle ScholarPubMed
Orkin, SH, Cheng, T-C, Antonarakis, SE, Kazazian, HH. Thalassaemia due to a mutation in the cleavage-polyadenylation signal of the human β-globin gene. EMBO J. 1985;4:453–456.Google ScholarPubMed
Maquat, . Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol. 2004;5(2):89–99.CrossRefGoogle ScholarPubMed
Lejeune, F, Maquat, . Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells. Curr Opin Cell Biol. 2005;17(3):309–315.CrossRefGoogle ScholarPubMed
Maquat, . Nonsense-mediated mRNA decay. Curr Biol. 2002;12(6):R196–197.CrossRefGoogle ScholarPubMed
Hall, GW, Thein, SL. Nonsense codon mutations in the terminal exon of the β-globin gene are not associated with a reduction in β-mRNA accumulation: a mechanism for the phenotype of dominant β-thalassemia. Blood. 1994;83:2031–2037.Google Scholar
Blacklock, HA, Case, J, Chan, T, et al. Novel sequence insertion in a Maori patient with transfusion-dependent beta-thalassaemia. Br J Haematol. 2005;131(3):400–402.CrossRefGoogle Scholar
Andersson, BA, Wering, ME, Luo, HY, et al. Sickle cell disease due to compound heterozygosity for Hb S and a novel 7.7-kb beta-globin gene deletion. Eur J Haematol. 2007;78(1):82–85.CrossRefGoogle Scholar
Codrington, JF, Li, H-W, Kutlar, F, Gu, L-H, Ramachandran, M, Huisman, THJ. Observations on the levels of Hb A2 in patients with different β thalassemia mutations and a d chain variant. Blood. 1990;76:1246–1249.Google Scholar
Weatherall, DJ, Clegg, JB, Knox-Macaulay, HHM, Bunch, C, Hopkins, CR, Temperley, IJ. A genetically determined disorder with features both of thalassaemia and congenital dyserythropoietic anaemia. Br J Haematol. 1973;24:681–702.CrossRefGoogle ScholarPubMed
Stamatoyannopoulos, G, Woodson, R, Papayannopoulou, T, Heywood, D, Kurachi, MS. Inclusion-body β-thalasemia trait. A form of β thalassemia producing clinical manifestations in simple heterozygotes. N Engl J Med. 1974;290:939–943.CrossRefGoogle Scholar
Thein, SL, Hesketh, C, Taylor, P, et al. Molecular basis for dominantly inherited inclusion body β thalassemia. Proc Natl Acad Sci USA. 1990;87:3924–3928.CrossRefGoogle ScholarPubMed
Coleman, MB, Steinberg, MH, Adams JG 3rd. Hemoglobin Terre Haute arginine beta 106. A posthumous correction to the original structure of hemoglobin Indianapolis. J Biol Chem. 1991;266(9):5798–5800.Google ScholarPubMed
Adams, JG, Boxer, , Baehner, RL, Forget, BG, Tsistrakis, GA, Steinberg, MH. Hemoglobin Indianapolis (β112(G14) arginine). An unstable β-chain variant producing the phenotype of severe β thalassemia. J Clin Invest. 1979;63:931–938.CrossRefGoogle Scholar
Baiget, M, Gomez Pereira, C, Jue, DL, Johnson, MH, McGuffey, JE, Moo-Penn, WF. A case of hemoglobin Indianapolis [beta 112(G14) Cys→Arg] in an individual from Cordoba, Spain. Hemoglobin. 1986;10(5):483–494.CrossRefGoogle Scholar
Biasi, R, Spiteri, D, Caldora, M, et al. Identification by fast atom bombardment mass spectrometry of Hb Indianapolis [beta 112(G14)Cys→Arg] in a family from Naples, Italy. Hemoglobin. 1988;12(4):323–336.CrossRefGoogle Scholar
Wajcman, H, Lahary, A, Prome, D, et al. Hb Mont Saint Aignan [beta128(H6)Ala→Pro]: a new unstable variant leading to chronic microcytic anemia. Hemoglobin. 2001;25(1):57–65.CrossRefGoogle ScholarPubMed
Thein, SL, Best, S, Sharpe, J, Paul, B, Clark, DJ, Brown, MJ. Hemoglobin Chesterfield (β 28 Leu→Arg) produces the phenotype of inclusion body β thalassemia. Blood. 1991;77:2791–2793.Google ScholarPubMed
Podda, A, Galanello, R, Maccioni, L, et al. Hemoglobin Cagliari (β 60 [E4] Val-Glu): a novel unstable thalassemic hemoglobinopathy. Blood. 1991;77:371–375.Google ScholarPubMed
Fucharoen, S, Fucharoen, G, Fukumaki, Y, et al. Three-base deletion in exon 3 of the β-globin gene produced a novel variant (βGunma) with a thalassemia-like phenotype. Blood. 1990;76:1894–1896.Google Scholar
Park, SS, Barnetson, R, Kim, SW, Weatherall, DJ, Thein, SL. A spontaneous deletion of β 33/34 Val in exon 2 of the β globin gene (Hb Korea) produces the phenotype of dominant β thalassaemia. Br J Haematol. 1991;78:581–582.CrossRefGoogle ScholarPubMed
Arjona, SN, Eloy-Garcia, JM, Gu, LH, Smetanina, NS, Huisman, THJ. The dominant β-thalassaemia in a Spanish family is due to a frameshift that introduces an extra CGG codon (arginine) at the 5′ end of the second exon. Br J Haematol. 1996;93:841–844.CrossRefGoogle Scholar
Çürük, MA, Molchanova, TP, Postnikov, YV, et al. β-thalassemia alleles and unstable hemoglobin types among Russian pediatric patients. Am J Hematol. 1994;46:329–332.CrossRefGoogle ScholarPubMed
Bunn, HF, Forget, BG. Hemoglobin: Molecular, Genetic and Clinical Aspects. Philadelphia: W.B. Saunders; 1986.Google Scholar
Öner, R, Öner, C, Wilson, JB, Tamagnini, GP, Ribeiro, LML, Huisman, THJ. Dominant β-thalassaemia trait in a Portuguese family is caused by a deletion of (G)TGGCTGGTGT(G) and an insertion of (G)GCAG(G) in codons 134, 135, 136 and 137 of the β-globin gene. Br J Haematol. 1991;79:306–310.CrossRefGoogle Scholar
Efremov, GD. Dominantly inherited beta-thalassemia. Hemoglobin. 2007;31(2):193–207.CrossRefGoogle ScholarPubMed
Ho, PJ, Wickramasinghe, SN, Rees, DC, Lee, MJ, Eden, A, Thein, SL. Erythroblastic inclusions in dominantly inherited β thalassaemias. Blood. 1997;89:322–328.Google Scholar
Adams, JGI, Steinberg, MH, Kazazian, HHJ. Isolation and characterization of the translation product of a β-globin gene nonsense mutation (β121 GAA→TAA). Br J Haematol. 1990;75:561–567.CrossRefGoogle Scholar
Prehu, C, Pissard, S, Al-Sheikh, M, et al. Two French Caucasian families with dominant thalassemia-like phenotypes due to hyper unstable hemoglobin variants: Hb Sainte Seve [codon 118 (−T)] and codon 127 [CAG→>TAG (Gln→stop]). Hemoglobin. 2005;29(3):229–333.CrossRefGoogle Scholar
Faustino, P, Osorio-Almeida, L, Romao, L, et al. Dominantly transmitted beta-thalassemia arising from the production of several aberrant mRNA species and one abnormal peptide. Blood. 1998;91(2):685–690.Google ScholarPubMed
Nagy, E, Maquat, . A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem Sci. 1998;23(6):198–199.CrossRefGoogle ScholarPubMed
Romao, L, Inacio, A, Santos, S, et al. Nonsense mutations in the human beta-globin gene lead to unexpected levels of cytoplasmic mRNA accumulation. Blood. 2000;96(8):2895–2901.Google ScholarPubMed
Olds, RJ, Sura, T, Jackson, B, Wonke, B, Hoffbrand, AV, Thein, SL. A novel δ0 mutation in cis with Hb Knossos: a study of different genetic interactions in three Egyptian families. Br J Haematol. 1991;78:430–436.CrossRefGoogle Scholar
Traeger-Synodinos, J, Tzetis, M, Kanavakis, E, Metaxotou-Mavromati, A, Kattamis, C. The Corfu δβ thalassaemia mutation in Greece: haematological phenotype and prevalence. Br J Haematol. 1991;79:302–305.CrossRefGoogle Scholar
Wainscoat, JS, Thein, SL, Wood, WG, et al. A novel deletion in the β globin gene complex. Ann NY Acad Sci. 1985;445:20–27.CrossRefGoogle ScholarPubMed
Chakalova, L, Osborne, CS, Dai, YF, et al. The Corfu deltabeta thalassemia deletion disrupts gamma-globin gene silencing and reveals post-transcriptional regulation of HbF expression. Blood. 2005;105(5):2154–2160.CrossRefGoogle ScholarPubMed
Galanello, R, Melis, MA, Podda, A, et al. Deletion δ-thalassemia: the 7.2 kb deletion of Corfu δ-thalassemia in a non-β-thalassemia chromosome. Blood. 1990;75:1747–1749.Google Scholar
Lapoumeroulie, C, Pagnier, J, Bank, A, Labie, D, Kirshnamoorthy, R. β-thalassemia due to a novel mutation in IVS-1 sequence donor site consensus sequence creating a restriction site. Biochem Biophys Res Commun. 1986;139:709–713.CrossRefGoogle ScholarPubMed
Ristaldi, MS, Casula, S, Porcu, S, Cao, A. Normal delta globin gene sequence in carrier of the silent −101 (C→T) beta-thalassemia mutation with normal HbA2 level. Am J Hematol. 2001;67(1):58.CrossRefGoogle Scholar
Moi, P, Faa, V, Marini, MG, et al. A novel silent beta–thalassemia mutation in the distal CACCC box affects the binding and responsiveness to EKLF. Br J Haematol. 2004; 126(6):881–884.CrossRefGoogle ScholarPubMed
Berg, P, Mittleman, M, Elion, J, Labie, D, Schechter, AN. Increased protein binding to a −530 mutation of the human β-globin gene associated with decreased β-globin synthesis. Am J Hematol. 1991;36:42–47.CrossRefGoogle ScholarPubMed
Thein, SL. Genetic modifiers of beta-thalassemia. Haematologica 2005;90(5):649–660.Google ScholarPubMed
Nagel, RL, Steinberg, MH. Hemoglobins of the embryo and fetus and minor hemoglobins of adults. In: Steinberg, MH, Forget, BG, Higgs, DR, Nagel, RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management. Cambridge: Cambridge University Press; 2001:252–276.Google Scholar
Huisman, THJ. Levels of Hb A2 in heterozygotes and homozygotes for beta-thalassemia mutations: influence of mutations in the CACCC and ATAAA motifs of the beta-globin gene promoter. Acta Haematol. 1997;98:187–194.CrossRefGoogle ScholarPubMed
Kimberland, ML, Divoky, V, Prchal, J, Schwahn, U, Berger, W, Kazazian, HHFull-length human L1 insertions retain the capacity for high frequency retrotransposition in cultured cells. Hum Mol Genet. 1999;8(8):1557–1560.CrossRefGoogle ScholarPubMed
Viprakasit, V, Gibbons, RJ, Broughton, BC, et al. Mutations in the general transcription factor TFIIH result in β-thalassaemia in individuals with trichothiodystrophy. Hum Mol Genet. 2001;10(24):2797–2802.CrossRefGoogle ScholarPubMed
Mehaffey, MG, Newton, AL, Gandhi, MJ, Crossley, M, Drachman, JG. X-linked thrombocytopenia caused by a novel mutation of GATA-1. Blood. 2001;98(9):2681–2688.CrossRefGoogle ScholarPubMed
Yu, C, Niakan, KK, Matsushita, M, Stamatoyannopoulos, G, Orkin, SH, Raskind, WH. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood. 2002;100(6):2040–2045.CrossRefGoogle ScholarPubMed
Murru, S, Loudianos, G, Porcu, S, et al. A β-thalassaemia phenotype not linked to the β-globin cluster in an Italian family. Br J Haematol. 1992;81:283–287.CrossRefGoogle ScholarPubMed
Pacheco, P, Peres, MJ, Faustino, P, et al. β-thalassaemia unlinked to the β-globin gene interacts with sickle-cell trait in a Portuguese family. Br J Haematol. 1995;91:85–89.CrossRefGoogle Scholar
Thein, SL, Wood, WG, Wickramasinghe, SN, Galvin, MC. β-thalassemia unlinked to the β-globin gene in an English family. Blood. 1993;82:961–967.Google Scholar
Badens, C, Mattei, MG, Imbert, AM, et al. A novel mechanism for thalassaemia intermedia. Lancet. 2002;359(9301):132–133.CrossRefGoogle ScholarPubMed
Galanello, R, Perseu, L, Perra, C, et al. Somatic deletion of the normal beta-globin gene leading to thalassaemia intermedia in heterozygous beta-thalassaemic patients. Br J Haematol. 2004;127(5):604–606.CrossRefGoogle ScholarPubMed
Malik, P, Arumugam, PI. Gene therapy for {beta}-thalassemia. Hematology Am Soc Hematol Educ Program. 2005:45–50.Google ScholarPubMed
Game, L, Bergounioux, J, Close, JP, Marzouka, BE, Thein, SL. A novel deletion causing (εγδβ)o thalassaemia in a Chilean family. Br J Haematol. 2003;123(1):154–159.CrossRefGoogle Scholar
Rooks, H, Bergounioux, J, Game, L, et al. Heterogeneity of the εγδβ-thalassaemias: characterization of three novel English deletions. Br J Haematol. 2005;128(5):722–729.CrossRefGoogle ScholarPubMed
Harteveld, CL, Osborne, CS, Peters, M, et al. Novel 112 kb (epsilonGgammaAgamma) deltabeta-thalassaemia deletion in a Dutch family. Br J Haematol. 2003;122(5):855–858.CrossRefGoogle Scholar
Harteveld, CL, Voskamp, A, Phylipsen, M, et al. Nine unknown rearrangements in 16p13.3 and 11p15.4 causing alpha- and beta-thalassaemia characterised by high resolution multiplex ligation-dependent probe amplification. J Med Genet. 2005;42(12):922–931.CrossRefGoogle ScholarPubMed
Jacob, GF, Raper, AB. Hereditary persistence of foetal haemoglobin production, and its interaction with the sickle-cell trait. Br J Haematol. 1958;4:138.CrossRefGoogle ScholarPubMed
Edington, GM, Lehmann, H. Expression of the sickle-cell gene in Africa. BMJ. 1955;i:1308–1311.CrossRefGoogle Scholar
Wheeler, JT, Krevans, JR. The homozygous state of persistent fetal hemoglobin and the interaction of persistent fetal hemoglobin with thalassemia. Bull Johns Hopkins Hosp. 1961;109:217.Google ScholarPubMed
Gerald, PS, Diamond, LK. The diagnosis of thalassemia trait by starch block electrophoresis of the hemoglobin. Blood. 1958;13:61–69.Google Scholar
Baglioni, C. The fusion of two peptide chains in hemoglobin Lepore and its interpretation as a genetic deletion. Proc Natl Acad Sci USA. 1962;48:1880–1886.CrossRefGoogle ScholarPubMed
Fessas, P, Stamatoyannopoulos, G, Karaklis, A. Hereditary persistence of foetal haemoglobin and its combination with alpha and beta-thalassaemia. In: 8th Congress of the European Society of Haematology. Vienna: Karger; 1961:302.Google Scholar
Zuelzer, WW, Robinson, AR, Booker, CR. Reciprocal relationship of hemoglobins A2 and F in beta chain thalassemias, a key to the genetic control of hemoglobin F. Blood. 1961; 17:393.Google Scholar
Brancati, C, Baglioni, C. Homozygous β thalassaemia (β-microcythaemia). Nature. 1966;212:262–264.CrossRefGoogle Scholar
Schroeder, WA, Huisman, THJ, Shelton, JR, et al. Evidence for multiple structural genes for the γ-chain of human fetal hemoglobin. Proc Natl Acad Sci USA. 1968;60:537–544.CrossRefGoogle ScholarPubMed
Fogarty, WM, Vedvick, TS, Itano, HA. Absence of haemoglobin A in an individual simultaneously heterozygous in the genes for hereditary persistence of foetal haemoglobin and beta-thalassaemia. Br J Haematol. 1974;26:527.CrossRefGoogle Scholar
Kosteas, T, Palena, A, Anagnou, NP. Molecular cloning of the breakpoints of the hereditary persistence of fetal hemoglobin type-6 (HPFH-6) deletion and sequence analysis of the novel juxtaposed region from the 3′ end of the β-globin gene cluster. Hum Genet. 1997;100:441–445.CrossRefGoogle ScholarPubMed
Huisman, THJ, Wrightstone, RN, Wilson, JB, Schroeder, WA, Kendall, AG. Hemoglobin Kenya, the product of fusion of γ and β polypeptide chains. Arch Biochem Biophys. 1972;153:850.CrossRefGoogle Scholar
Kendall, AG, Ojwang, PJ, Schroeder, WA, Huisman, THJ. Hemoglobin Kenya, the product of a γ-β fusion gene: studies of the family. Am J Hum Genet. 1973;25:548.Google Scholar
Ojwang, PJ, Nakatsuji, T, Gardiner, MB, Reese, AL, Gilman, JG, Huisman, THJ. Gene deletion as the molecular basis for the Kenya-Gγ-HPFH condition. Hemoglobin. 1983;7:115–123.CrossRefGoogle ScholarPubMed
Kosteas, T, Moschonas, N, Anagnou, NP. The molecular basis for the phenotypic differences between δβ-thalassemia and HPFH: the role of the two silencers upstream of the δ-globin gene. Blood. 1996;88:105a.Google Scholar
Atweh, GF, Zhu, X-X, Brickner, HW, Dowling, CH, Kazazian, HH, Forget, BG. The β-globin gene on the Chinese δβ-thalassemia chromosome carries a promoter mutation. Blood. 1987;70:1470–1474.Google Scholar
Zeng, Y-T, Huang, S-Z, Chen, B, et al. Hereditary persistence of fetal hemoglobin or (δβ)o-thalassemia: three types observed in South-Chinese families. Blood. 1985;66:1430–1435.Google ScholarPubMed
Forget, BG, Hillman, DG, Lazarus, H, et al. Absence of messenger RNA and gene DNA for β-globin chains in hereditary persistence of fetal hemoglobin. Cell. 1976;7:323–329.CrossRefGoogle ScholarPubMed
Fritsch, EF, Lawn, RM, Maniatis, T. Characterisation of deletions which affect the expression of fetal globin genes in man. Nature. 1979;279:598.CrossRefGoogle ScholarPubMed
Orkin, SH, Alter, BP, Altay, C, et al. Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion. N Engl J Med. 1978;299:166–172.CrossRefGoogle ScholarPubMed
Acquaye, CTA, Oldham, JH, Konotey-Ahulu, FID. Blood donor homozygous for hereditary persistence of fetal haemoglobin. Lancet. 1977;i:796–797.CrossRefGoogle Scholar
Huisman, TH. The first homozygote for the hereditary persistence of fetal hemoglobin observed in the southeastern United States. Hemoglobin. 1981;5(4):411–416.Google ScholarPubMed
Kutlar, A, Gardiner, MB, Headlee, MG, et al. Heterogeneity in the molecular basis of three types of hereditary persistence of fetal hemoglobin and the relative synthesis of the Gγ and Aγ types of γ chain. Biochem Genet. 1984;22:21.CrossRefGoogle Scholar
Ringelhann, B, Konotey-Ahulu, FID, Lehmann, H, Lorkin, PA. A Ghanaian adult, homozygous for hereditary persistence of foetal haemoglobin and heterozygous for elliptocytosis. Acta Haematol. 1970;43:100.CrossRefGoogle ScholarPubMed
Tuan, D, Murnane, MJ, Riel, JK, Forget, BG. Heterogeneity in the molecular basis of hereditary persistence of fetal haemoglobin. Nature. 1980;285:335.CrossRefGoogle ScholarPubMed
Ferrara, M, Matarese, SM, Francese, M, et al. Hematological and molecular analysis of beta-thalassemia and Hb Lepore in Campania, Italy. Hemoglobin. 2001;25(1):29–34.CrossRefGoogle ScholarPubMed
Ribeiro, ML, Cunha, E, Goncalves, P, et al. Hb Lepore-Baltimore (δ68Leu-β84Thr) and Hb Lepore-Washington-Boston (δ87Gin-βIVS-II-8) in Central Portugal and Spanish Alta Extremadura. Hum Genet. 1997;99:669–673.CrossRefGoogle Scholar
Waye, JS, Walker, L, Kyriakopoulou, LG, Potter, MA, Eng, B. Characterisation of a novel 49.3 kb Gγ(Aγδβ)0-thalassaemia deletion in seven families of Asian descent. Br J Haematol. 2007;138(1):125–126.CrossRefGoogle Scholar
Wood, WG, Clegg, JB, Weatherall, DJ, et al. Gγδβ thalassaemia and GγHPFH (Hb Kenya type). Comparison of two new cases. J Med Genet. 1977;14:237.CrossRefGoogle Scholar
Wood, WG, Macrae, IA, Darbre, PD, Clegg, JB, Weatherall, DJ. The British type of non-deletion HPFH: characterisation of developmental changes in vivo and erythroid growth in vitro. Br J Haematol. 1982;50:401.CrossRefGoogle Scholar
Henthorn, PS, Smithies, O, Mager, DL. Molecular analysis of deletions in the human β-globin gene cluster: deletion junctions and locations of breakpoints. Genomics. 1990;6:226–237.CrossRefGoogle ScholarPubMed
Huisman, THJ, Schroeder, WA, Efremov, GD, et al. The present status of the heterogeneity of fetal hemoglobin in β-thalassemia; an attempt to unify some observations in thalassemia and related conditions. Ann NY Acad Sci. 1974; 232:107–124.CrossRefGoogle ScholarPubMed
Bernards, R, Flavell, RA. Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin. Nucl Acids Res. 1980;8:1521.CrossRefGoogle ScholarPubMed
Calzolari, R, McMorrow, T, Yannoutsos, N, Langeveld, A, Grosveld, F. Deletion of a region that is a candidate for the difference between the deletion forms of hereditary persistence of fetal hemoglobin and δβ-thalassemia affects β- but not γ-globin gene expression. EMBO J. 1999;18:949–958.CrossRefGoogle Scholar
Gribnau, J, Diderich, K, Pruzina, S, Calzolari, R, Fraser, P. Intergenic transcription and developmental remodeling of chromatin subdomains in the human beta-globin locus. Mol Cell. 2000;5(2):377–386.CrossRefGoogle ScholarPubMed
Gaensler, KM, Zhang, Z, Lin, C, Yang, S, Hardt, K, Flebbe-Rehwaldt, L. Sequences in the Aγδ intergenic region are not required for stage-specific regulation of the human beta-globin gene locus. Proc Natl Acad Sci USA. 2003;100(6):3374–3379.CrossRefGoogle Scholar
Townes, TM, Behringer, RR. Human globin locus activation region (LAR): Role in temporal control. Trends Genet. 1990;6:219–223.CrossRefGoogle ScholarPubMed
Wood, WG. Hb F production in adult life. In: Stamatoyannopoulos, G, Nienhuis, AW, eds. Hemoglobin Switching, Part B: Cellular and Molecular Mechanisms. New York: AR Liss; 1989:251–267.Google Scholar
Arcasoy, MO, Romana, M, Fabry, ME, Skarpidi, E, Nagel, RL, Forget, BG. High levels of human γ-globin gene expression in adult mice carrying a transgene of deletion-type hereditary persistence of fetal hemoglobin. Mol Cell Biol. 1997;17:2076–2089.CrossRefGoogle ScholarPubMed
Dillon, N, Grosveld, F. Human γ-globin genes silenced independently of other genes in β-globin locus. Nature. 1991;350:252–254.CrossRefGoogle ScholarPubMed
Peterson, KR, Li, QL, Clegg, CH, et al. Use of yeast artificial chromosomes (YACs) in studies of mammalian development: production of β-globin locus YAC mice carrying human globin developmental mutants. Proc Natl Acad Sci USA. 1995;92:5655–5659.CrossRefGoogle ScholarPubMed
Feingold, EA, Forget, BG. The breakpoint of a large deletion causing hereditary persistence of fetal hemoglobin occurs within an erythroid DNA domain remote from the β-globin gene cluster. Blood. 1989;74:2178–2186.Google ScholarPubMed
Tuan, D, Feingold, E, Newman, M, Weissman, SM, Forget, BG. Different 3′ end points of deletions causing δβ-thalassemia and hereditary persistence of fetal hemoglobin; Implications for the control of γ-globin gene expression in man. Proc Natl Acad Sci USA. 1983;80:6937.CrossRefGoogle Scholar
Elder, JT, Forrester, WC, Thompson, C, et al. Translocation of an erythroid-specific hypersensitive site in deletion-type hereditary persistence of fetal hemoglobin. Mol Cell Biol. 1990;10:1382–1389.CrossRefGoogle ScholarPubMed
Forrester, WC, Epner, E, Driscoll, MC, et al. A deletion of the human β-globin locus activation region causes a major alteration in chromatin structure and replication across the entire β-globin locus. Genes Dev. 1990;4:1637–1649.CrossRefGoogle Scholar
Xiang, P, Han, H, Barkess, G, et al. Juxtaposition of the HPFH2 enhancer is not sufficient to reactivate the gamma-globin gene in adult erythropoiesis. Hum Mol Genet. 2005; 14(20):3047–56.CrossRefGoogle Scholar
Anagnou, NP, Perez-Stable, C, Gelinas, R, et al. Sequences located 3′ to the breakpoint of the hereditary persistence of fetal hemoglobin-3 deletion exhibit enhancer activity and can modify the developmental expression of the human fetal Aγ-globin gene in transgenic mice. J Biol Chem. 1995; 270:10256–10263.CrossRefGoogle Scholar
Katsantoni, EZ, Langeveld, A, Wai, AW, et al. Persistent gamma-globin expression in adult transgenic mice is mediated by HPFH-2, HPFH-3, and HPFH-6 breakpoint sequences. Blood. 2003;102(9):3412–3419.CrossRefGoogle ScholarPubMed
Fessas, P. The beta-chain thalassaemias. In: Lehmann, H, Betke, K, eds. Haemoglobin Colloquium. Vienna: Thieme; 1961:90.Google Scholar
Fessas, P, Stamatoyannopoulos, G. Hereditary persistence of fetal hemoglobin in Greece. A study and a comparison. Blood. 1964;24:223.Google ScholarPubMed
Huisman, THJ, Schroeder, WA, Stamatoyannopoulos, G, et al. Nature of fetal hemoglobin in the Greek type of hereditary persistence of fetal hemoglobin with and without concurrent β-thalassemia. J Clin Invest. 1970;49:1035.CrossRefGoogle ScholarPubMed
Huisman, THJ, Miller, A, Schroeder, WA. A Gγ type of the hereditary persistence of fetal hemoglobin with beta chain production in cis. Am J Hum Genet. 1975;27:765–777.Google Scholar
Weatherall, DJ, Cartner, R, Clegg, JB, Wood, WG, Macrae, IA, MacKenzie, A. A form of hereditary persistence of fetal haemoglobin characterised by uneven cellular distribution of haemoglobin F and the production of haemoglobins A and A2 in homozygotes. Br J Haematol. 1975;29:205.CrossRefGoogle Scholar
Jones, RW, Old, JM, Wood, WG, Clegg, JB, Weatherall, DJ. Restriction endonuclease maps of the β-like globin gene cluster in the British and Greek forms of HPFH, and for one example of Gγ+ HPFH. Br J Haematol. 1982;50:415–422.CrossRefGoogle Scholar
Collins, FS, Stoeckert, CJ, Serjeant, GR, Forget, BG, Weissman, SM. Gγ+ hereditary persistence of fetal hemoglobin: cosmid cloning and identification of a specific mutation 5′ to the Gγ gene. Proc Natl Acad Sci USA. 1984;81:4894–4898.CrossRefGoogle Scholar
Collins, FS, Metherall, JE, Yamakawa, M, Pan, J, Weissman, SM, Forget, BG. A point mutation in the Aγ-globin gene promoter in Greek hereditary persistence of fetal haemoglobin. Nature. 1985;313:325.CrossRefGoogle Scholar
Gelinas, R, Bender, M, Lotshaw, C, Waber, P, Kazazian, HHJ, Stamatoyannopoulos, G. Chinese Aγ fetal hemoglobin: C to T substitution at position −196 of the Aγ gene promoter. Blood. 1986;67:1777–1779.Google Scholar
Giglioni, B, Casini, C, Mantovani, R, et al. A molecular study of a family with Greek hereditary persistence of fetal hemoglobin and β-thalassemia. EMBO J. 1984;3:2641–2645.Google ScholarPubMed
Metherall, JE, Gillespie, FP, Forget, BG. Analyses of linked β-globin genes suggest that nondeletion forms of hereditary persistence of fetal hemoglobin are bona fide switching mutants. Am J Hum Genet. 1988;42:476–481.Google ScholarPubMed
Tate, VE, Wood, WG, Weatherall, DJ. The British form of hereditary persistence of fetal haemoglobin results from a single base mutation adjacent to an S1 hypersensitive site 5′ to the Aγ globin gene. Blood. 1986;68:1389–1393.Google Scholar
Waber, PG, Bender, MA, Gelinas, RE, et al. Concordance of a point mutation 5′ to the Aγ globin gene in Aγβ+ HPFH in Greeks. Blood. 1986;67:551–554.Google Scholar
Berry, M, Grosveld, F, Dillon, N. A single point mutation is the cause of the Greek form of hereditary persistence of fetal haemoglobin. Nature. 1992;358:499–502.CrossRefGoogle ScholarPubMed
Starck, J, Sarkar, R, Romana, M, et al. Developmental regulation of human γ- and β-globin genes in the absence of the locus control region. Blood. 1994;84:1656–1665.Google ScholarPubMed
Bacolla, A, Ulrich, MJ, Larson, JE, Ley, TJ, Wells, RD. An intramolecular triplex in the human gamma-globin 5′-flanking region is altered by point mutations associated with hereditary persistence of fetal hemoglobin. J Biol Chem. 1995; 270(41):24556–24563.CrossRefGoogle ScholarPubMed
Fischer, K-D, Nowock, J. The T→C substitution at −198 of the Aγ-globin gene associated with the British form of HPFH generates overlapping recognition sites for two DNA-binding proteins. Nucl Acids Res. 1990;18:5685–5693.CrossRefGoogle Scholar
Fucharoen, S, Shimizu, K, Fukumaki, Y. A novel C-T transition within the distal CCAAT motif of the Gγ-globin gene in the Japanese HPFH: implication of factor binding in elevated fetal globin expression. Nucl Acids Res. 1990;18:5245–5253.CrossRefGoogle Scholar
Gumucio, DL, Rood, KL, Gray, TA, Riordan, MF, Sartor, CI, Collins, FS. Nuclear proteins that bind the human γ-globin gene promoter: alterations in binding produced by point mutations associated with hereditary persistence of fetal hemoglobin. Mol Cell Biol. 1988;8:5310–5322.CrossRefGoogle ScholarPubMed
Gumucio, DL, Rood, KL, Blanchard-McQuate, KL, Gray, TA, Saulino, A, Collins, FS. Interaction of Sp1 with the human γ globin promoter: binding and transactivation of normal and mutant promoters. Blood. 1991;78:1853–1863.Google ScholarPubMed
Jane, SM, Gumucio, DL, Ney, PA, Cunningham, JM, Nienhuis, AW. Methylation-enhanced binding of Sp1 to the stage selector element of the human γ-globin gene promoter may regulate developmental specificity of expression. Mol Cell Biol. 1993;13(6):3272–3281.CrossRefGoogle Scholar
Mantovani, R, Malgaretti, N, Nicolis, S, Ronchi, A, Giglioni, B, Ottolenghi, S. The effects of HPFH mutations in the human γ-globin promoter on binding of ubiquitous and erythroid specific nuclear factors. Nucl Acids Res. 1988;16:7783–7797.CrossRefGoogle ScholarPubMed
Mantovani, R, Superti-Furga, G, Gilman, J, Ottolenghi, S. 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. Nucl Acids Res. 1989;17(16):6681–91.CrossRefGoogle Scholar
Martin, DIK, Tsai, S-F, Orkin, SH. Increased γ-globin expression in a nondeletion HPFH mediated by an erythroid-specific DNA-binding factor. Nature. 1989;338:435–438.CrossRefGoogle Scholar
Ronchi, A, Nicolis, S, Santoro, C, Ottolenghi, S. Increased Sp1 binding mediates erythroid-specific overexpression of a mutated (HPFH) γ-globin promoter. Nucl Acids Res. 1989;17: 10231–10241.CrossRefGoogle Scholar
Superti-Furga, G, Barberis, A, Schaffner, G, Busslinger, M. The −117 mutation in Greek HPFH affects the binding of three nuclear factors to the CCAAT region of the γ-globin gene. EMBO J. 1988;7:3099–30107.Google ScholarPubMed
Sykes, K, Kaufman, R. A naturally occurring gamma globin gene mutation enhances SP1 binding activity. Mol Cell Biol. 1990;10:95–102.CrossRefGoogle ScholarPubMed
Ulrich, MJ, Gray, WJ, Ley, TJ. An intramolecular DNA triplex is disrupted by point mutations associated with hereditary persistence of fetal hemoglobin. J Biol Chem. 1992;267:18649–18658.Google ScholarPubMed
Gumucio, DL, Lockwood, WK, Weber, JL, et al. The −175 T-C mutation increases promoter strength in erythroid cells: correlaion with evolutionary conservation of binding sites for two trans-acting factors. Blood. 1990;75:756–761.Google Scholar
Lanclos, KD, Michael, SK, Gu, TC, Howard, EF, Stoming, TA, Huisman, THJ. Transient chloramphenicol acetyltransferase expression of the Gγ globin gene 5′-flanking regions containing substitutions of C→T at position −158, G→A at position −161, and T→A at position −175 in K562 cells. Biochim Biophys Acta. 1989;1008:109–112.CrossRefGoogle Scholar
Motum, PI, Lindeman, R, Harvey, MP, Trent, RJ. Comparative studies of nondeletional HPFH γ-globin gene promoters. Exp Hematol. 1993;21:852–858.Google ScholarPubMed
Nicolis, S, Ronchi, A, Malgaretti, N, Mantovani, R, Giglioni, B, Ottolenghi, S. Increased erythroid-specific expression of a mutated HPFH γ globin promoter requires the erythroid factor NFE-1. Nucl Acids Res. 1989;17:5509–5516.CrossRefGoogle ScholarPubMed
Rixon, MW, Gelinas, RE. A fetal globin gene mutation in Aγ nondeletion HPFH increases promoter strength in a non-erythroid cell. Mol Cell Biol. 1988;8:713–721.CrossRefGoogle Scholar
Ulrich, MJ, Ley, TJ. Function of normal and mutated γ-globin gene promoters in electroporated K562 erythroleukemia cells. Blood. 1990;75:990–999.Google ScholarPubMed
Roberts, NA, Sloane-Stanley, JA, Sharpe, JA, Stanworth, SJ, Wood, WG. Globin gene switching in transgenic mice carrying HS2-globin gene constructs. Blood. 1997;89:713–723.Google ScholarPubMed
Ronchi, A, Berry, M, Raguz, S, et al. Role of the duplicated CCAAT box region in γ-globin gene regulation and hereditary persistence of fetal haemoglobin. EMBO J. 1996;15:143–149.Google ScholarPubMed
Wijgerde, M, Grosveld, F, Fraser, P. Transcription complex stability and chromatin dynamics. Nature. 1995;377:209–213.CrossRefGoogle ScholarPubMed
Craig, JE, Rochette, J, Fisher, CA, et al. Haemoglobin switch: dissecting the loci controlling fetal haemoglobin production on chromosomes 11p and 6q by the regressive approach. Nat Genet. 1996;12:58–64.CrossRefGoogle Scholar
Craig, JE, Rochette, J, Sampietro, M, et al. Genetic heterogeneity in heterocellular hereditary persistence of fetal hemoglobin. Blood. 1997;90:428–434.Google ScholarPubMed
Giampaolo, A, Mavilio, F, Sposi, NM, et al. Heterocellular HPFH: molecular mechanisms of abnormal γ gene expression in association with β thalassemia and linkage relationship with the β globin gene cluster. Hum Genet. 1984;66:151–156.CrossRefGoogle ScholarPubMed
Gianni, AM, Bregni, M, Cappellini, MD, et al. A gene controlling fetal hemoglobin expression in adults is not linked to the non-α globin cluster. EMBO J. 1983;2:921–926.Google Scholar
Martinez, G, Novelletto, A, Di Renzo, A, Felicetti, L, Colombo, B. A case of hereditary persistence of fetal hemoglobin caused by a gene not linked to the β-globin cluster. Hum Genet. 1989;82:335–337.CrossRefGoogle Scholar
Oppenheim, A, Yaari, A, Rund, D, et al. Intrinsic potential for high fetal hemoglobin production in a Druz family with β-thalassemia is due to an unlinked genetic determinant. Hum Genet. 1990;86:175–180.CrossRefGoogle Scholar
Seltzer, WK, Abshire, TC, Lane, PA, Roloff, JS, Githens, JH. Molecular genetic studies in black families with sickle cell anemia and unusually high levels of fetal hemoglobin. Hemoglobin. 1992;16:363–377.CrossRefGoogle ScholarPubMed
Thein, SL, Weatherall, DJ. A non-deletion hereditary persistence of fetal hemoglobin (HPFH) determinant not linked to the β-globin gene complex. In: Stamatoyannopoulos, G, Nienhuis, AW, eds. Hemoglobin Switching, Part B: Cellular and Molecular Mechanisms. New York: Alan R. Liss; 1989:97–112.Google Scholar
Miyoshi, K, Kaneto, Y, Kawai, H, Huisman, THJ. X-linked dominant control of F-cells in normal adult life. Blood. 1988; 72:1854.Google ScholarPubMed
Dover, GJ, Smith, KD, Chang, YC, et al. Fetal hemoglobin levels in sickle cell disease and normal individuals are partially controlled by an X-linked gene located at Xp22.2. Blood. 1992;80:816–824.Google ScholarPubMed
Chang, YC, Smith, KD, Moore, RD, Serjeant, GR, Dover, GJ. An analysis of fetal hemoglobin variation in sickle cell disease: the relative contributions of the X-linked factor, β-globin haplotypes, α-globin gene number, gender and age. Blood. 1995;85:1111–1117.Google ScholarPubMed
Thein, SL, Sampietro, M, Rohde, K, Weatherall, DJ, Lathrop, GM, Demenais, F. Detection of a major gene for heterocellular HPFH after accounting for genetic modifiers. American Journal of Hum Genet. 1994;54:214–228.Google Scholar
Close, J, Game, L, Clark, B, Bergounioux, J, Gerovassili, A, Thein, SL. Genome annotation of a 1.5 Mb region of human chromosome 6q23 encompassing a quantitative trait locus for fetal hemoglobin expression in adults. BMC Genomics. 2004;5(1):33.CrossRefGoogle ScholarPubMed
Garner, CP, Tatu, T, Best, S, Creary, L, Thein, SL. Evidence of genetic interaction between the beta-globin complex and chromosome 8q in the expression of fetal hemoglobin. Am J Hum Genet. 2002;70(3):793–799.CrossRefGoogle ScholarPubMed
Garner, C, Menzel, S, Martin, C, et al. Interaction between two quantitative trait loci affects fetal haemoglobin expression. Ann Hum Genet. 2005;69(Pt 6):707–714.CrossRefGoogle ScholarPubMed
Menzel, S, Garner, C, Gut, I, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nat Genet. 2007;39(10):1197–1199.CrossRefGoogle ScholarPubMed
Gilman, JG, Huisman, THJ. DNA sequence variation associated with elevated fetal Gγ globin production. Blood. 1985;66:783–787.Google Scholar
Labie, D, Pagnier, J, Lapoumeroulie, C, et al. Common haplotype dependency of high Gγ-globin gene expression and high Hb F levels in β-thalassemia and sickle cell anemia patients. Proc Natl Acad Sci USA. 1985;82:2111–2114.CrossRefGoogle Scholar
Labie, D, Dunda-Belkhodja, O, Rouabhi, F, Pagnier, J, Ragusa, A, Nagel, RL. The −158 site 5′ to the Gγ gene and Gγ expression. Blood. 1985;66:1463–1465.Google Scholar
Gilman, JG, Huisman, THJ. Two independentgenetic factors in the β-globin gene cluster are associated with high Gγ-levels in the HbF of SS patients. Blood. 1984;64:452–457.Google ScholarPubMed
Elion, J, Berg, PE, Lapoumeroulie, C, et al. DNA sequence variation in a negative control region 5′ to the β-globin gene correlates with the phenotypic expression of the βS mutation. Blood. 1992;79:787–792.Google Scholar
Lanclos, KD, Oner, C, Dimovski, AJ, Gu, Y-C, Huisman, THJ. Sequence variations in the 5′ flanking and IVS-II regions of the Gγ- and Aγ-globin genes of βS chromosomes with five different haplotypes. Blood. 1991;77:2488–2496.Google Scholar
Pissard, S, Beuzard, Y. A potential regulatory region for the expression of fetal hemoglobin in sickle cell disease. Blood. 1994;84:331–338.Google ScholarPubMed
Beris, P, Kitundu, MN, Baysal, E, et al. Black β-thalassemia homozygotes with specific sequence variations in the 5′ hypersensitive site-2 of the locus control region have high levels of fetal hemoglobin. Am J Hematol. 1992;41:97–101.CrossRefGoogle ScholarPubMed
Merghoub, T, Perichon, B, Maier-Redesperger, M, et al. Variation of fetal hemoglobin and F-cell number with the LCR-HS2 polymorphism in nonanemic individuals. Blood. 1996;87:2607–2609.Google ScholarPubMed
Öner, C, Dimovski, AJ, Altay, C, et al. Sequence variations in the 5′ hypersensitive site-2 of the locus control region of βS chromosomes are associated with different levels of fetal globin in hemoglobin S homozygotes. Blood. 1992;79:813–819.Google Scholar
Eng, B, Walker, L, Nakamura, LM, et al. Three new beta-globin gene promoter mutations identified through newborn screening. Hemoglobin. 2007;31(2):129–134.CrossRefGoogle ScholarPubMed
Sadiq, MF, Eigel, A, Horst, J. Spectrum of beta-thalassemia in Jordan: identification of two novel mutations. Am J Hematol. 2001;68(1):16–22.CrossRefGoogle ScholarPubMed
Akar, E, Ozdemir, S, Hakki Timur, I, Akar, N. First observation of homozygous hemoglobin hamadan (B 56 (D7) GLY-ARG) and beta thalassemia (−29 G >A)-hemoglobin Hamadan combination in a Turkish family. Am J Hematol. 2003;74(4):280–282.CrossRefGoogle Scholar
Ba, RK, Reiss, UM, Luo, HY, Ware, RE, Chui, DH. Beta-thalassemia intermedia due to compound heterozygosity for two beta-globin gene promoter mutations, including a novel TATA box deletion. Pediatr Blood Cancer. 2008;50(2):363–366.Google Scholar
Angioletti, M, Lacerra, G, Sabato, V, Carestia, C. Beta + 45 G→C: a novel silent beta-thalassaemia mutation, the first in the Kozak sequence. Br J Haematol. 2004;124(2):224–231.CrossRefGoogle ScholarPubMed
Waye, JS, Walker, L, Patterson, M, Chui, DH. Identification of two new beta-thalassemia splice mutations: IVS-I-1 (G→>C) and IVS-I (−2) (A→C). Hemoglobin. 2002;26(1):87–89.CrossRefGoogle Scholar
Fujihara, N, Tozuka, M, Ueno, I, et al. Novel beta-thalassemia trait (IVS I-1 G→C) in a Japanese family. Am J Hematol. 2003;72(1):64–66.CrossRefGoogle Scholar
Basak, AN. The molecular pathology of beta-thalassemia in Turkey: the Bogazici university experience. Hemoglobin. 2007;31(2):233–241.CrossRefGoogle ScholarPubMed
Rojnuckarin, P, Settapiboon, R, Vanichsetakul, P, Sueblinvong, T, Sutcharitchan, P. Severe β0 thalassemia/hemoglobin E disease caused by de novo 22-base pair duplication in the paternal allele of beta globin gene. Am J Hematol. 2007;82(7):663–665.CrossRefGoogle Scholar
Cross, TJ, Berry, PA, Akbar, N, Wendon, J, Thein, SL, Harrison, PM. Sickle liver disease–An unusual presentation in a compound heterozygote for HbS and a novel beta-thalassemia mutation. Am J Hematol. 2007;82(9):852–854.CrossRefGoogle Scholar
Lacan, P, Becchi, M, Zanella-Cleon, I, et al. Two new beta-chain variants: Hb Tripoli [beta26(B8)Glu→Ala] and Hb Tizi-Ouzou [beta29(B11)Gly→Ser]. Hemoglobin. 2004;28(3):205–212.CrossRefGoogle Scholar
Jacquette, A, Roux, G, Lacombe, C, Goossens, M, Pissard, S. Compound heterozygosity for two new mutations in the beta-globin gene [codon 9 (+TA) and polyadenylation site (AATAAA→AAAAAA)] leads to thalassemia intermedia in a Tunisian patient. Hemoglobin. 2004;28(3):243–248.CrossRefGoogle Scholar
Ma, SK, Lee, ACW, Chan, AYY, Chan, LC. A novel AATAAA→ CATAAA mutation at the polyadenylation site of the β-globin gene. Br J Haematol. 2001;115(1):231–231.Google ScholarPubMed
Waye, JS, Eng, B, Patterson, M, Reis, MD, Macdonald, D, Chui, DH. Novel beta-thalassemia mutation in a beta-thalassemia intermedia patient. Hemoglobin. 2001;25(1):103–105.CrossRefGoogle Scholar
Lacan, P, Ponceau, B, Aubry, M, Francina, A. Mild Hb S-beta(+)-thalassemia with a deletion of five nucleotides at the polyadenylation site of the beta-globin gene. Hemoglobin. 2003;27(4):257–259.CrossRefGoogle ScholarPubMed
Knott, M, Ramadan, KM, Savage, G, et al. Novel and Mediterranean beta thalassemia mutations in the indigenous Northern Ireland population. Blood Cells Mol Dis. 2006;36(2):265–268.CrossRefGoogle ScholarPubMed
Grignoli, CR, Carvalho, MH, Kimura, EM, et al. Beta0-thalassemia resulting from a novel mutation: beta66/u→stop codon. Eur J Haematol. 2000;64(2):137–138.CrossRefGoogle ScholarPubMed
Patterson, M, Walker, L, Chui, DH, Cohen, AR, Waye, JS. Identification of a new beta-thalassemia nonsense mutation [codon 59 (AAG→TAG)]. Hemoglobin. 2003;27(3):201–203.CrossRefGoogle Scholar
Mo, QH, Li, XR, Li, CF, He, YL, Xu, XM. A novel frameshift mutation (+G) at codons 15/16 in a beta0 thalassaemia gene results in a significant reduction of beta globin mRNA values. J Clin Pathol. 2005;58(9):923–926.CrossRefGoogle Scholar
Lacan, P, Aubry, M, Couprie, N, Francina, A. Two new betao-thalassemic mutations: a deletion (-CC) at codon 142 or overlapping codons 142–143, and an insertion (+T) at codon 45 or overlapping codons 44–45(45–46 of the beta-globin gene. Hemoglobin. 2007;31(2):159–165.CrossRefGoogle ScholarPubMed
Nadkarni, A, Sakaguchi, T, Takaku, H, et al. A novel betao-thalassemia mutation at codon 55 (−A) and a rare 17 bp deletion at codons 126–131 in the Indian population. Hemoglobin. 2002;26(1):41–47.CrossRefGoogle Scholar
Shaji, RV, Gerard, N, Krishnamoorthy, R, Srivastava, A, Chandy, M. A novel beta-thalassemia mutation in an Asian Indian. Hemoglobin. 2002;26(1):49–57.CrossRefGoogle Scholar
Foulon, K, Rochette, J, Cadet, E. A novel beta-thalassemic allele due to a two nucleotide deletion: beta76 (−GC). Hemoglobin. 2007;31(1):31–37.CrossRefGoogle Scholar
Shaji, RV, Srivastava, A, Krishnamoorthy, R, Chandy, M. Coexistence of a novel beta-globin gene deletion (codons 81–87) with the codon 30 (G→C) mutation in an Indian patient with beta0-thalassemia. Hemoglobin. 2002;26(3):237–243.CrossRefGoogle Scholar
Flatz, G, Wilke, K, Syagailo, YV, Eigel, A, Horst, J. Beta-thalassemia in the German population: mediterranean, Asian and novel mutations. Mutations in brief no. 228. Online. Hum Mutat. 1999;13(3):258.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
Giordano, PC, Addo-Daaku, A, Sander, MJ, et al. The rare Hb Showa-Yakushiji [beta110(G12)Leu→Pro, CTG→CCG] in combination with an alpha gene triplication found in a Dutch patient during her first pregnancy examination. Hemoglobin. 2007;31(2):167–171.CrossRefGoogle Scholar
Keser, I, Kayisli, OG, Yesilipek, A, Ozes, ON, Luleci, G. Hb Antalya [codons 3–5 (Leu-Thr-Pro→Ser-Asp-Ser)]: a new unstable variant leading to chronic microcytic anemia and high Hb A2. Hemoglobin. 2001;25(4):369–373.CrossRefGoogle Scholar
Hall, GW, Franklin, IM, Sura, T, Thein, SL. A novel mutation (nonsense β127) in exon 3 of the β globin gene produces a variable thalassaemia phenotype. Br J Haematol. 1991;79:342–344.CrossRefGoogle Scholar
Luo, HY, Tang, W, Eung, SH, et al. Dominantly inherited beta thalassaemia intermedia caused by a new single nucleotide deletion in exon 2 of the beta globin gene: Hb morgantown (beta91 CTG>CG). J Clin Pathol. 2005;58(10):1110–1112.CrossRefGoogle Scholar
Lahr, G, Brintrup, J, Over, S, Feurle, GE, Debatin, K-M, Kohne, E. Codon 104(→G), a heterozygous frameshift mutation in exon 2 of HBB, resulted in a dominantly inherited beta-phenotype with mild anemia in a German kindred, and thalassemia intermedia in the index patient. A co-inherited a gene triplication, long-term transfusion therapy, and ineffective erythropoiesis were confounding factors. Haematologica. 2007;92:1264–1265.CrossRefGoogle Scholar
Waye, JS, Walker, L, Lafferty, J, Lemire, EG, Chui, DH. Dominant beta-thalassemia due to a newly identified frameshift mutation in exon 3 (codon 113, GTG→Tg). Hemoglobin. 2002;26(1):83–86.CrossRefGoogle Scholar
Ropero, P, Villegas, A, Martinez, M, Ataulfo Gonzalez Fernandez, F, Benavente, C, Mateo, M. A deletion of 11 bp (CD 131–134) in exon 3 of the beta-globin gene produces the phenotype of inclusion body beta-thalassemia. Ann Hematol. 2005;84(9):584–587.CrossRefGoogle ScholarPubMed
Weinstein, BI, Erramouspe, B, Albuquerque, DM, et al. Hb Florida: a novel elongated C-terminal beta-globin variant causing dominant beta-thalassemia phenotype. Am J Hematol. 2006;81(5):358–360.CrossRefGoogle ScholarPubMed

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