A line of transgenic mice (αHβS-11; where αH is human α-globin) was created in which the human βS and human α2 globin genes, each linked to the β-globin locus control region, were cointegrated into the mouse genome. On a normal genetic background, the transgenic mice produced 36% human βS-globin chains with an αH/βS ratio of 1.3. Higher levels of βS were achieved by breeding the transgenic mice with mutant mice carrying a mouse βmajor-globin gene deletion. Mice heterozygous for the βmajor; deletion (αHβS[βMD]; MD, mouse deletion) had 54% βSwith an αH/βS ratio of 1.0; mice homozygous for the βmajor; deletion (αHβS[βMDD]) had 72.5% βS and an αH/βS ratio of 0.73. Because mouse a chains inhibit hemoglobin (Hb) S polymerization, we bred the mice to heterozygosity for a mouse α-globin deletion. These mice (αHβS[αMDβ MDD]) had an increased αH/βSratio of 0.89 but expressed 65% βS. Expression of the human genes cured the thalassemic phenotype associated with the murine βmajor deletion. Transgenic αHβS[βMDD] mice had normal hematocrit and Hb and somewhat elevated reticulocytes (6% vs. 3% for control), whereas the mice carrying the α-globin deletion (αHβS[βMDD]) had a normal hematocrit and Hb and more elevated retieulocytes (10.3 ± 7.6% vs. 3.4 ± 1.0%). Expression of the transgene restored a normal distribution of erythrocyte densities when compared to thalassemic mice; however, the average mean corpuscular Hb concentration of αHβS[βMDD] mice increased to 35.7 g/dl (vs. control 33.7 g/dl) whereas that of αHβS[βMDD mice was further elevated to 36.3 g/dl. The intrinsic oxygen affinity was increased in transgenic mouse erythrocytes at 280 milliosmolal, and the Po2 at midsaturation of αHβS[βMDD erythrocytes was higher than that of αHβS[βMDD cells (37.4 ± 2 vs. 33.5 ± 1 mmHg). The higher values of the mean corpuscular Hb concentration and intrinsic PO2 at midsaturation, which favor in vivo sickling, may explain the slightly more severe hematological picture in αHβS[βMDD mice. We conclude that the transgenic mouse with high Hb S expression does not exhibit adult anemia but does have abnormal hematological features: increased erythrocyte density, high oxygen affinity, and reticulocytosis with increased stress retieulocytes.
|Original language||English (US)|
|Number of pages||5|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Jan 1 1992|
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