High Levels Of Human γ-globin Are Expressed In Adult Mice Carrying A Transgene Of The Brazilian Type Of Hereditary Persistence Of Fetal Hemoglobin (aγ -195)

Hereditary persistence of fetal hemoglobin (HPFH) is characterized by increased levels of Hb F during adult life. Nondeletional forms of HPFH are characterized by single base mutations in the Aγ and Gγ promoters, resulting in an increase of Hb F ranging from 3 to 20 in heterozygotes. Many point mutations in this region have been described, including the Aγ -195 (C>G) mutation that causes the Brazilian type of HPFH (HPFH-B). To better understand this mechanism, we have developed HPFH-B transgenic mice. mRNA levels of human γ-globin of -195 transgenic mice were clearly higher when compared with control transgenic mice bearing a wild type sequence of the γ promoter. Thus, our data indicate that the -195 mutation is the unique cause of elevation of Hb F in Brazilian HPFH. These results could provide us with an opportunity to study the modifying effects of the Hb F in the phenotype of sickle cell disease and β-thalassemia (β-thal). © Informa UK Ltd.336439447Olave, I.A., Doneanu, C., Fang, X., Stamatoyannopoulos, G., Li, Q., Purification and identification of proteins that bind to the hereditary persistence of fetal hemoglobin -198 mutation in the g-globin gene promoter (2007) J Biol Chem., 282 (2), pp. 853-862Stamatoyannopoulos, G., Grosveld, F.G., (2001) Hemoglobin Switching, 2. , 3rd ed. Philadelphia: W.B. Saunders CompanyTakahashi, T., Schreiber, R., Krieger, J.E., Saad, S.T., Costa, F.F., Analysis of the mechanism of action of the Brazilian type (Ag ?195 C G) of hereditary persistence of fetal hemoglobin (2003) Eur J Haematol., 71 (6), pp. 418-424Katsantoni, E.Z., Langeveld, A., Wai, A.W., Persistent g-globin expression in adult transgenic mice is mediated by HPFH-2 HPFH-3 and HPFH-6 breakpoint sequences (2003) Blood, 102 (9), pp. 3412-3419Forget, B.G., Molecular basis of hereditary persistence of fetal hemoglobin (1998) Ann NY Acad Sci., 850, pp. 38-44Keys, J.R., Tallack, M.R., Zhan, Y., A mechanism for Ikaros regulation of human globin gene switching (2008) Br J Haematol., 141 (3), pp. 398-406Tasiopoulou, M., Boussiou, M., Sinopoulou, K., Moraitis, G., Loutradi-Anagnostou, A., Karababa, P., Gg -196 CT Ag ?201 CT: Two novel mutations in the promoter region of the g-globin genes associated with nondeletional hereditary persistence of fetal hemoglobin in Greece (2008) Blood Cells Mol Dis., 40 (3), pp. 320-322Costa, F.F., Zago, M.A., Cheng, G., Nechtman, J.F., Stoming, T.A., Huisman, T.H.J., The Brazilian type of nondeletional Ag-HPFH has a C?G substitution at nucleotide ?195 of the Ag-globin gene (1990) Blood, 76 (9), pp. 1896-1990Schreiber, R., Goncalves, M.S., Junqueira, M.L., Saad, S.T., Krieger, J.E., Costa, F.F., The Ag -195 (CG) mutation in hereditary persistence of fetal hemoglobin is not associated with activation of a reporter gene in vitro (2001) Braz J Med Biol Res., 34 (4), pp. 489-492Enver, T., Raich, N., Ebens, A.J., Papayannopoulou, T., Costantini, F., Stamatoyannopoulos, G., Developmental regulation of human fetal-to-adult globin gene switching in transgenic mice (1990) Nature, 344 (6264), pp. 309-313Sabatino, D., Cline, A., Gallagher, P., Substitution of the human b-spectrin promoter for the human Ag-globin promoter prevents silencing of a linked human b-globin gene in transgenic mice (1998) Mol Cell Biol., 18 (11), pp. 6634-6640Zoueva, O., Garrett, L., Bodine, D., Rodgers, G., BP1 motif in the human b-globin promoter affects b-globin expression during embryonic/fetal erythropoiesis in transgenic mice bearing the human b-globin gene (2008) Blood Cells Mol Dis., 41 (3), pp. 244-251Gallagher, P., Sabatino, D., Basseres, D., Erythrocyte ankyrin promoter mutations associated with recessive hereditary spherocytosis cause significant abnormalities in ankyrin expression (2001) J Biol Chem., 276 (45), pp. 41683-41689Liu, L.R., Du, Z.W., Zhao, H.L., T to C substitution at -175 or -173 of the g-globin promoter affects GATA-1 and Oct-1 binding in vitro differently but can independently reproduce the hereditary persistence of fetal hemoglobin phenotype in transgenic mice (2005) J Biol Chem., 280 (9), pp. 7452-7459Gumucio, D.L., Rood, K.L., Blanchard-Mcquate, K.L., Gray, T.A., Saulino, A., Collins, F.S., Interaction of Sp1 with the human g globin promoter: Binding and transactivation of normal and mutant promoters (1991) Blood, 78 (7), pp. 1853-1863Berry, M., Grosveld, F., Dillon, N., A single point mutation is the cause of the Greek form of hereditary persistence of fetal haemoglobin (1992) Nature, 358 (6386), pp. 499-502Peterson, K.R., Li, Q.L., Clegg, C.H., Use of yeast artificial chromosomes (YACs) in studies of mammalian development: Production of b-globin locus YAC mice carrying human globin developmental mutants (1995) Proc Natl Acad Sci USA., 92 (12), pp. 5655-5659Li, Q., Duan, Z.J., Stamatoyannopoulos, G., Analysis of the mechanism of action of non-deletion hereditary persistence of fetal hemoglobin mutants in transgenic mice (2001) EMBO J., 20 (1-2), pp. 157-16