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 ^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).

Keywords:

• Hb F
• Hereditary persistence of fetal hemoglobin (HPFH)
• Transgenic mice
• −195 Mutation
• γ-Globin

ACKNOWLEDGMENTS

We thank Qiliang Li (Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA) for providing the μLCRAγψβδβ cosmid, Vinicius Motta and Umea Transgene Core Facility (Umea, Sweden) for help in the generation of the −195PHHF transgenic mice and Dr. Nicola Conran (Hematology and Hemotherapy Center, Universidade Estadual de Campinas, São Paulo, Brazil) for English revision. This study was funded by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP grants 02/13801-7 and 05/51222-7)

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.