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Hemoglobin C in transgenic mice: effect of HbC expression from founders to full mouse globin knockouts
M E Fabry1, J R Romero, S M Suzuka
1Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, New York 10461, USA. fabry@aecom.yu.edu
Insights
Hemoglobin C (HbC) disease increases red blood cell density, causing pathology. This study created a HbC mouse model that closely mimics human HbC disease red cell changes, validating its use for studying disease mechanisms.
Area of Science:
- Hematology
- Genetics
- Pathophysiology
Background:
- Homozygous hemoglobin C (HbC) disease elevates red blood cell density, a key factor in SC disease pathology.
- The precise mechanisms behind HbC-induced red cell density increase remain undefined.
Purpose of the Study:
- To develop and characterize a novel mouse model expressing human hemoglobin C (HbC).
- To investigate the pathophysiological consequences of HbC expression on red blood cell properties.
Main Methods:
- Generated transgenic HbC mice with varying levels of human alpha and beta(C)-globin expression.
- Utilized gene knockouts for mouse alpha- and beta-globins.
- Analyzed red blood cell parameters including MCH, MCHC, K:Cl cotransport, and morphology via SEM.
Main Results:
- Transgenic HbC mice with high beta(C) expression exhibited increased MCHC, dense reticulocytes, and elevated K:Cl cotransport.
- Red blood cell morphology in these mice showed striking similarities to human HbC disease cells.
- Mice expressing exclusively HbC without mouse globins were not thalassemic, with minimally reduced MCH.
Conclusions:
- The developed HbC mouse model accurately recapitulates key red blood cell abnormalities seen in human HbC disease.
- These findings validate the mouse model's utility for studying HbC-induced red cell pathophysiology and related gene interactions.
Abstract:
When present in the homozygous form, hemoglobin C (HbC, CC disease) increases red cell density, a feature that is the major factor underlying the pathology in patients with SC disease (Fabry et al., JCI 70, 1315, 1982). The basis for the increased red cell density has not yet been fully defined. We have generated a HbC mouse in which the most successful founder expresses 56% human alpha and 34% human beta(C). We introduced knockouts (KO) of mouse alpha- and beta-globins in various combinations. In contrast to many KO mice, all partial KOs have normal MCH. Full KOs that express exclusively HbC and no mouse globins have minimally reduced MCH (13. 7 +/- 0.3 pg/cell vs 14.5 +/- 1.0 for C57BL/6) and a ratio of beta- to alpha-globin chains of 0.88 determined by chain synthesis; hence, these mice are not thalassemic. Mice with beta(C) > 30% have increased MCHC, dense reticulocytes, and increased K:Cl cotransport. Red cell morphology studied by SEM is strikingly similar to that of human CC cells with bizarre folded cells. We conclude that red cells of these mice have many properties that closely parallel the pathology of human disease in which HbC is the major determinant of pathogenesis. These studies also establish the existence of the interactions with other gene products that are necessary for pleiotropic effects (red cell dehydration, elevated K:Cl cotransport, morphological changes) that are also present in these transgenic mice, validating their usefulness in the analysis of pathophysiological events induced by HbC in red cells.