A second generation transgenic mouse model expressing both hemoglobin S (HbS) and HbS-antilles results in increased phenotypic severity

M. E. Fabry, A. Sengupta, S. M. Suzuka, F. Costantini, E. M. Rubin, J. Hofrichter, G. Christoph, E. Manci, D. Culberson, S. M. Factor, R. L. Nagel

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79 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2419-2428
Number of pages10
Issue number6
StatePublished - Sep 15 1995
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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