title: A transgenic mouse model expressing exclusively human hemoglobin E: indications of a mild oxidative stress.
abstract: Hemoglobin (Hb) E (β26 Glu→Lys) is the most common abnormal hemoglobin (Hb) variant in the world. Homozygotes for HbE are mildly thalassemic as a result of the alternate splice mutation and present with a benign clinical picture (microcytic and mildly anemic) with rare clinical symptoms. Given that the human red blood cell (RBC) contains both HbE and excess α-chains along with minor hemoglobins, the consequence of HbE alone on RBC pathophysiology has not been elucidated. This becomes critical for the highly morbid β(E)-thalassemia disease. We have generated transgenic mice exclusively expressing human HbE (HbEKO) that exhibit the known aberrant splicing of β(E) globin mRNA, but are essentially non-thalassemic as demonstrated by RBC α/β (human) globin chain synthesis. These mice exhibit hematological characteristics similar to presentations in human EE individuals: microcytic RBC with low MCV and MCH but normal MCHC; target RBC; mild anemia with low Hb, HCT and mildly elevated reticulocyte levels and decreased osmotic fragility, indicating altered RBC surface area to volume ratio. These alterations are correlated with a mild RBC oxidative stress indicated by enhanced membrane lipid peroxidation, elevated zinc protoporphyrin levels, and by small but significant changes in cardiac function. The C57 (background) mouse and full KO mouse models expressing HbE with the presence of HbS or HbA are used as controls. In select cases, the HbA full KO mouse model is compared but found to be limited due to its RBC thalassemic characteristics. Since the HbEKO mouse RBC lacks an abundance of excess α-chains that would approximate a mouse thalassemia (or a human thalassemia), the results indicate that the observed in vivo RBC mild oxidative stress arises, at least in part, from the molecular consequences of the HbE mutation.
authors.affiliation: Department of Medicine/Hematology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Qiuying
authors.initials: Q
authors.lastname: Chen
authors.forename: Mary E
authors.initials: ME
authors.lastname: Fabry
authors.forename: Anne C
authors.initials: AC
authors.lastname: Rybicki
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Suzuka
authors.forename: Tatiana C
authors.initials: TC
authors.lastname: Balazs
authors.forename: Zipora
authors.initials: Z
authors.lastname: Etzion
authors.forename: Kitty
authors.initials: K
authors.lastname: de Jong
authors.forename: Edna K
authors.initials: EK
authors.lastname: Akoto
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Canterino
authors.forename: Dhananjay K
authors.initials: DK
authors.lastname: Kaul
authors.forename: Frans A
authors.initials: FA
authors.lastname: Kuypers
authors.forename: David
authors.initials: D
authors.lastname: Lefer
authors.forename: Eric E
authors.initials: EE
authors.lastname: Bouhassira
authors.forename: Rhoda Elison
authors.initials: RE
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D001947:Breeding; D004909:Erythrocyte Indices; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006446:Hemoglobin E / Q000235:genetics* / Q000378:metabolism*; D006455:Hemoglobins, Abnormal / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009996:Osmotic Fragility; D018384:Oxidative Stress; D055542:alpha-Globins / Q000096:biosynthesis; D055544:beta-Globins / Q000096:biosynthesis
chemical_list: D006455:Hemoglobins, Abnormal; D055542:alpha-Globins; D055544:beta-Globins; D006446:Hemoglobin E