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)

Abstract

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 (A)gamma and (G)gamma 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 (A)gamma -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 gamma-globin of -195 transgenic mice were clearly higher when compared with control transgenic mice bearing a wild type sequence of the gamma 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 beta-thalassemia (beta-thal).

Induction of Fetal HemoglobinIn VivoMediated by a Syntheticγ-Globin Zinc Finger Activator

“…However, the human A γ -globin gene functions as a fetal gene in mice, and the HPFH phenotype is recapitulated in transgenic mice containing −117, −175, −195, or −566 A γ -globin HPFH point-mutant globin constructs or β -YACs ([23, 27, 32–34], unpublished data). These models have been utilized extensively to understand the function of cis -acting elements and trans -acting factors within the γ -globin locus, including their potential effects in restoring γ -globin expression in adult erythropoiesis [23, 27, 32–34]. Recently, enforced expression of the trans -acting factor TR2/TR4 orphan nuclear receptor was shown to increase γ -globin gene expression in adult erythroid cells of the humanized SCD mouse model [10].…”

Correlations with Point Mutations and Severity of Hemolitic Anemias: The Example of Hereditary Persistence of Fetal Hemoglobin with Sickle Cell Anemia and Beta Thalassemia

“…This observation was supported by an increase in  globin gene expression in yolk sac, fetal liver and other organs of these mice compared to expression in mice carrying the wild  globin cluster. The results showed that the presence of the mutation -195 together with the entire  globin cluster is sufficient to develop the phenotype of ndHPFH-B in mice (da Cunha et al 2009). Even with these detailed studies, the complete mechanism involved in the reactivation of the globin gene in the Brazilian type  A ndHPFH is not elucidated.…”

Estudo dos potenciais mecanismos moleculares relacionados à expressão gênica diferencial em portadores de persistência hereditária de hemoglobina fetal não delecional tipo brasileira

“…Esses estudos visam identificar elementos gênicos associados à ativação ou à inativação dos genes das globinas e os mecanismos envolvidos na regulação do switching da HbF para a HbA (Bunn & Forget, 1986;Stamatoyannopoulos & Grosveld, 2001) et al, 2003). No estudo in vivo usando camundongo transgênico foi verificado que a simples presença da mutação -195 é suficiente para desenvolver o fenótipo de ndPHHF-B (Cunha et al, 2009).…”