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A second generation transgenic mouse model expressing both hemoglobin S
(HbS) and HbS-Antilles results in increased phenotypic severity
ME Fabry, A Sengupta, SM Suzuka, F Costantini, EM Rubin, J Hofrichter, G Christoph, E Manci, D Culberson and SM Factor
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY
10461, USA.
We report on a second generation of transgenic mice produced by crossing a
transgenic mouse line expressing high levels of human alpha and beta S
chains (alpha H beta S [beta MDD]) with a line expressing human alpha and
beta S-Antilles (beta SAnt). We hypothesized that mice expressing both
hemoglobins (Hbs) would have a more severe phenotype because the reduced
oxygen affinity and solubility of the beta S- Antilles might enhance the
rate and extent of polymer formation. We obtained mice that expressed both
beta S and beta S-Antilles. The doubly transgenic mice that are
heterozygous for deletion of mouse beta Major (beta MD) occurred with
reduced frequency and those that are homozygous for deletion of mouse beta
Major (beta MDD) occurred at a much reduced frequency and suffered early
mortality. Human alpha was 58% of all alpha globin for all animals, whereas
beta S and beta S- Antilles were 34% and 28% of all beta globins for beta
MD mice and 42% and 36% for beta 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 alpha H beta S [beta 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 alpha H beta S beta S-Ant[beta MDD] mice). The median mean corpuscular
hemoglobin concentration of doubly transgenic mice was higher than that of
alpha H beta S[beta MDD] mice with a variable number of very dense cells.
Delay times for polymerization of Hb in red blood cells from alpha H beta S
beta S-Ant[beta MDD] mice were shorter than those of alpha H beta S[beta
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.
Volume 86,
Issue 6,
pp. 2419-2428,
09/15/1995
Copyright © 1995 by The American Society of Hematology
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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January 1, 1997;
11(1):
11 - 43.
[PDF]
|
|
|
|
|
