High expression of human βS-and α-globins in transgenic mice: Erythrocyte abnormalities, organ damage, and the effect of hypoxia

Mary E. Fabry, Frank Costantini, Agathe Pachnis, Sandra M. Suzuka, Norman Bank, Hagop S. Aynedjian, Steven M. Factor, Ronald L. Nagel

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14 Scopus citations


A line of transgenic mice with two cointegrated transgenes, the human βS- and α2-globin genes, linked to the β-globin locus control region was produced and bred with mice carrying a deletion of the mouse βmajor-globin gene. In transgenic mice homozygous for the βmajor deletion (αHβSMDD]; where αH is human α-globin and MD is mouse deletion), 72.5 ± 2.4% (mean ± SD) of the β-chains are βS and the ratio of αH- to βS-globin was 0.73. Introduction of a heterozygous mouse α-globin deletion into mice homozygous for the βmajor deletion (αHβSMDβMDD) resulted in 65.1 ± 8.5% βS and a human α/β ratio of 0.89 ± 0.2. Sickling occurs in 95% of erythrocytes from orαHβSMDD] mice after slow deoxygenation. Transmission electron microscopy revealed polymer fiber formation but not fascicles of fiber. Increased organ weight was noted in lung, spleen, and kidney of transgenic mice vs. controls that may be due to hypertrophy or increased blood volume in the lungs and/or increased tissue water content. The hemoglobin content of lung, spleen, and kidney was also elevated in transgenic animals due to trapped hemoglobin and/or increased blood volume. When transgenic and control mice were examined by magnetic resonance imaging at 9.4 tesla, some transgenic animals had enlarged kidneys with prolonged relaxation time, consistent with increased organ weight and water content. The glomerular filtration rate was elevated in transgenic animals, which is characteristic of young sickle cell patients. Furthermore, exposure to hypoxia resulted in significantly decreased hematocrit, increased erythrocyte density, and induced a urineconcentrating defect. We conclude that the transgenic mouse line reported here has chronic organ damage and further hematological and organ dysfunction can be induced by hypoxia.

Original languageEnglish (US)
Pages (from-to)12155-12159
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
StatePublished - 1992
Externally publishedYes

ASJC Scopus subject areas

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