Hemoglobin C in transgenic mice: Effect of HbC expression from founders tofull mouse globin knockouts

dWhen present in the homozygous form, hemoglobin C (HbC, CC disease) increa ses red cell density, a feature that is the major factor underlying the pat hology 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 mou se alpha- and beta -globins in various combinations. In contrast to many KO mice, all partial KOs have normal MCH. Full KOs that express exclusively H bC 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 incr eased K:Cl cotransport. Red cell morphology studied by SEM is strikingly si milar 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 pat hology of human disease in which HbC is the major determinant of pathogenes is. These studies also establish the existence of the interactions with oth er gene products that are necessary for pleiotropic effects (red cell dehyd ration, elevated K:Cl cotransport, morphological changes) that are also pre sent in these transgenic mice, validating their usefulness in the analysis of pathophysiological events induced by HbC in red cells. (C) 2000 Academic Press.