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Towards a mouse model for sickle cell disease: HB SAD
M Trudel1, M C Garel, N Saadane
1Department of Genetics and Development, Columbia University, New York, NY 10032.
Nouvelle Revue Francaise D'Hematologie
|January 1, 1990
Summary
Transgenic mice expressing a modified human hemoglobin S (beta SAD) gene showed minimal sickling in vitro but experienced developmental issues and high mortality under hypoxia, indicating potential in vivo risks.
Area of Science:
- Hematology
- Genetics
- Transgenic Animal Models
Background:
- Sickle cell disease is caused by human hemoglobin S.
- Transgenic mice are used to study human diseases.
- Previous models achieved high expression of human hemoglobin S.
Purpose of the Study:
- To create a modified beta S gene (beta SAD) for inducing hemoglobin polymerization in transgenic mice.
- To investigate the in vivo effects of SAD hemoglobin, including sickling, developmental impact, and hypoxia-induced mortality.
Main Methods:
- Construction of a modified beta S gene (beta SAD) with two additional mutations.
- Generation of transgenic mice expressing the beta SAD gene.
- In vitro deoxygenation of erythrocytes to induce sickling.
- Observation of SAD mice for anemia, incidence in progeny, and mortality under hypoxic conditions.
Main Results:
- Transgenic SAD mice showed a low percentage of irreversible sickle cells in vitro.
- Anemia in neonates and reduced incidence of SAD animals suggest developmental toxicity.
- Hypoxia induced high mortality in adult SAD mice, indicating vaso-occlusive events.
Conclusions:
- The beta SAD gene induces polymerization and sickling in vitro.
- SAD hemoglobin exhibits deleterious effects during development and induces vaso-occlusive events under hypoxia in vivo.
- This model provides insights into sickle cell disease pathogenesis and potential therapeutic targets.