TY - JOUR
T1 - A second generation transgenic mouse model expressing both hemoglobin S (HbS) and HbS-antilles results in increased phenotypic severity
AU - Fabry, M. E.
AU - Sengupta, A.
AU - Suzuka, S. M.
AU - Costantini, F.
AU - Rubin, E. M.
AU - Hofrichter, J.
AU - Christoph, G.
AU - Manci, E.
AU - Culberson, D.
AU - Factor, S. M.
AU - Nagel, R. L.
PY - 1995/9/15
Y1 - 1995/9/15
N2 - We report on a second generation of transgenic mice produced by crossing a transgenic mouse line expressing high levels of human α and β(s) chains (α(H)β(s)[β(MDD)]) with a line expressing human α and β(S-Antilles) (β(SAnt)). We hypothesized that mice expressing both hemoglobins (Hbs) would have a more severe phenotype because the reduced oxygen affinity and solubility of the β(S-Antilles) might enhance the rate and extent of polymer formation. We obtained mice that expressed both β(s) and β(S-Antilles). The doubly transgenic mice that are heterozygous for deletion of mouse β(Major) (β(MD)) occurred with reduced frequency and those that are homozygous for deletion of mouse β(Major) (β(MDD) occurred at a much reduced frequency and suffered early mortality. Human α was 58% of all α globin for all animals, whereas β(s) and β(S-Antilles) were 34% and 28% of all β globins for β(MD) mice and 42% and 36% for β(MDD) mice. Hematocrit, Hb, and mean corpuscular Hb were normal for all transgenic mice, but reticulocyte levels were higher for the doubly transgenic mice versus α(H)β(s)[β(MDD)] mice older than 30 days (10.0% ± 1.0% v 4.3% ± 0.4%; P < .001, mean ± SE, n = 20 and n = 10, respectively) and control mice (3.9% ± 0.4%). Reticulocytosis was more severe in mice less than 30 days old (>20% for α(H)β(s)β(S- Ant)[β(MDD)] mice). The median mean corpuscular hemoglobin concentration of doubly transgenic mice was higher than that of α(H)β(s)[β(MDD)] mice with a variable number of very dense cells. Delay times for polymerization of Hb in red blood cells from α(H)β(s)β(S-Ant)[β(MDD)] mice were shorter than those of α(H)β(s)[β(MDD)] mice, and there were fewer cells with delay times greater than 100 seconds. Urine-concentrating ability in control mice under ambient conditions is 2,846 ± 294 mOsm and was reduced 30% to 1,958 ± 240 mOsm, P < 4 x 10-8 in all mice expressing both transgenes. We conclude that doubly transgenic mice have a more severe phenotype than either of the two parental lines. These mice may be suitable for validating therapeutic intervention in sickle cell disease.
AB - We report on a second generation of transgenic mice produced by crossing a transgenic mouse line expressing high levels of human α and β(s) chains (α(H)β(s)[β(MDD)]) with a line expressing human α and β(S-Antilles) (β(SAnt)). We hypothesized that mice expressing both hemoglobins (Hbs) would have a more severe phenotype because the reduced oxygen affinity and solubility of the β(S-Antilles) might enhance the rate and extent of polymer formation. We obtained mice that expressed both β(s) and β(S-Antilles). The doubly transgenic mice that are heterozygous for deletion of mouse β(Major) (β(MD)) occurred with reduced frequency and those that are homozygous for deletion of mouse β(Major) (β(MDD) occurred at a much reduced frequency and suffered early mortality. Human α was 58% of all α globin for all animals, whereas β(s) and β(S-Antilles) were 34% and 28% of all β globins for β(MD) mice and 42% and 36% for β(MDD) mice. Hematocrit, Hb, and mean corpuscular Hb were normal for all transgenic mice, but reticulocyte levels were higher for the doubly transgenic mice versus α(H)β(s)[β(MDD)] mice older than 30 days (10.0% ± 1.0% v 4.3% ± 0.4%; P < .001, mean ± SE, n = 20 and n = 10, respectively) and control mice (3.9% ± 0.4%). Reticulocytosis was more severe in mice less than 30 days old (>20% for α(H)β(s)β(S- Ant)[β(MDD)] mice). The median mean corpuscular hemoglobin concentration of doubly transgenic mice was higher than that of α(H)β(s)[β(MDD)] mice with a variable number of very dense cells. Delay times for polymerization of Hb in red blood cells from α(H)β(s)β(S-Ant)[β(MDD)] mice were shorter than those of α(H)β(s)[β(MDD)] mice, and there were fewer cells with delay times greater than 100 seconds. Urine-concentrating ability in control mice under ambient conditions is 2,846 ± 294 mOsm and was reduced 30% to 1,958 ± 240 mOsm, P < 4 x 10-8 in all mice expressing both transgenes. We conclude that doubly transgenic mice have a more severe phenotype than either of the two parental lines. These mice may be suitable for validating therapeutic intervention in sickle cell disease.
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U2 - 10.1182/blood.v86.6.2419.bloodjournal8662419
DO - 10.1182/blood.v86.6.2419.bloodjournal8662419
M3 - Article
C2 - 7662990
AN - SCOPUS:0029144487
SN - 0006-4971
VL - 86
SP - 2419
EP - 2428
JO - Blood
JF - Blood
IS - 6
ER -