High expression of human βS- And α-globins in transgenic mice

Hemoglobin composition and hematological consequences

Mary E. Fabry, Ronald L. Nagel, Agathe Pachnis, Sandra M. Suzuka, Frank Costantini

Research output: Contribution to journalArticle

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Abstract

A line of transgenic mice (αHβS-11; where αH is human α-globin) was created in which the human βS and human α2 globin genes, each linked to the β-globin locus control region, were cointegrated into the mouse genome. On a normal genetic background, the transgenic mice produced 36% human βS-globin chains with an αHS ratio of 1.3. Higher levels of βS were achieved by breeding the transgenic mice with mutant mice carrying a mouse βmajor-globin gene deletion. Mice heterozygous for the βmajor; deletion (αHβSMD]; MD, mouse deletion) had 54% βSwith an αHS ratio of 1.0; mice homozygous for the βmajor; deletion (αHβSMDD]) had 72.5% βS and an αHS ratio of 0.73. Because mouse a chains inhibit hemoglobin (Hb) S polymerization, we bred the mice to heterozygosity for a mouse α-globin deletion. These mice (αHβSMDβ MDD]) had an increased αHSratio of 0.89 but expressed 65% βS. Expression of the human genes cured the thalassemic phenotype associated with the murine βmajor deletion. Transgenic αHβSMDD] mice had normal hematocrit and Hb and somewhat elevated reticulocytes (6% vs. 3% for control), whereas the mice carrying the α-globin deletion (αHβSMDD]) had a normal hematocrit and Hb and more elevated retieulocytes (10.3 ± 7.6% vs. 3.4 ± 1.0%). Expression of the transgene restored a normal distribution of erythrocyte densities when compared to thalassemic mice; however, the average mean corpuscular Hb concentration of αHβSMDD] mice increased to 35.7 g/dl (vs. control 33.7 g/dl) whereas that of αHβSMDD mice was further elevated to 36.3 g/dl. The intrinsic oxygen affinity was increased in transgenic mouse erythrocytes at 280 milliosmolal, and the Po2 at midsaturation of αHβSMDD erythrocytes was higher than that of αHβSMDD cells (37.4 ± 2 vs. 33.5 ± 1 mmHg). The higher values of the mean corpuscular Hb concentration and intrinsic PO2 at midsaturation, which favor in vivo sickling, may explain the slightly more severe hematological picture in αHβSMDD mice. We conclude that the transgenic mouse with high Hb S expression does not exhibit adult anemia but does have abnormal hematological features: increased erythrocyte density, high oxygen affinity, and reticulocytosis with increased stress retieulocytes.

Original languageEnglish (US)
Pages (from-to)12150-12154
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number24
StatePublished - 1992

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Globins
Transgenic Mice
Hemoglobins
Erythrocytes
Sickle Hemoglobin
Erythrocyte Indices
Hematocrit
Locus Control Region
Reticulocytosis
Oxygen
Reticulocytes
Normal Distribution
Gene Deletion
Transgenes
Polymerization

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

High expression of human βS- And α-globins in transgenic mice : Hemoglobin composition and hematological consequences. / Fabry, Mary E.; Nagel, Ronald L.; Pachnis, Agathe; Suzuka, Sandra M.; Costantini, Frank.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 24, 1992, p. 12150-12154.

Research output: Contribution to journalArticle

Fabry, Mary E. ; Nagel, Ronald L. ; Pachnis, Agathe ; Suzuka, Sandra M. ; Costantini, Frank. / High expression of human βS- And α-globins in transgenic mice : Hemoglobin composition and hematological consequences. In: Proceedings of the National Academy of Sciences of the United States of America. 1992 ; Vol. 89, No. 24. pp. 12150-12154.
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abstract = "A line of transgenic mice (αHβS-11; where αH is human α-globin) was created in which the human βS and human α2 globin genes, each linked to the β-globin locus control region, were cointegrated into the mouse genome. On a normal genetic background, the transgenic mice produced 36{\%} human βS-globin chains with an αH/βS ratio of 1.3. Higher levels of βS were achieved by breeding the transgenic mice with mutant mice carrying a mouse βmajor-globin gene deletion. Mice heterozygous for the βmajor; deletion (αHβS[βMD]; MD, mouse deletion) had 54{\%} βSwith an αH/βS ratio of 1.0; mice homozygous for the βmajor; deletion (αHβS[βMDD]) had 72.5{\%} βS and an αH/βS ratio of 0.73. Because mouse a chains inhibit hemoglobin (Hb) S polymerization, we bred the mice to heterozygosity for a mouse α-globin deletion. These mice (αHβS[αMDβ MDD]) had an increased αH/βSratio of 0.89 but expressed 65{\%} βS. Expression of the human genes cured the thalassemic phenotype associated with the murine βmajor deletion. Transgenic αHβS[βMDD] mice had normal hematocrit and Hb and somewhat elevated reticulocytes (6{\%} vs. 3{\%} for control), whereas the mice carrying the α-globin deletion (αHβS[βMDD]) had a normal hematocrit and Hb and more elevated retieulocytes (10.3 ± 7.6{\%} vs. 3.4 ± 1.0{\%}). Expression of the transgene restored a normal distribution of erythrocyte densities when compared to thalassemic mice; however, the average mean corpuscular Hb concentration of αHβS[βMDD] mice increased to 35.7 g/dl (vs. control 33.7 g/dl) whereas that of αHβS[βMDD mice was further elevated to 36.3 g/dl. The intrinsic oxygen affinity was increased in transgenic mouse erythrocytes at 280 milliosmolal, and the Po2 at midsaturation of αHβS[βMDD erythrocytes was higher than that of αHβS[βMDD cells (37.4 ± 2 vs. 33.5 ± 1 mmHg). The higher values of the mean corpuscular Hb concentration and intrinsic PO2 at midsaturation, which favor in vivo sickling, may explain the slightly more severe hematological picture in αHβS[βMDD mice. We conclude that the transgenic mouse with high Hb S expression does not exhibit adult anemia but does have abnormal hematological features: increased erythrocyte density, high oxygen affinity, and reticulocytosis with increased stress retieulocytes.",
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N2 - A line of transgenic mice (αHβS-11; where αH is human α-globin) was created in which the human βS and human α2 globin genes, each linked to the β-globin locus control region, were cointegrated into the mouse genome. On a normal genetic background, the transgenic mice produced 36% human βS-globin chains with an αH/βS ratio of 1.3. Higher levels of βS were achieved by breeding the transgenic mice with mutant mice carrying a mouse βmajor-globin gene deletion. Mice heterozygous for the βmajor; deletion (αHβS[βMD]; MD, mouse deletion) had 54% βSwith an αH/βS ratio of 1.0; mice homozygous for the βmajor; deletion (αHβS[βMDD]) had 72.5% βS and an αH/βS ratio of 0.73. Because mouse a chains inhibit hemoglobin (Hb) S polymerization, we bred the mice to heterozygosity for a mouse α-globin deletion. These mice (αHβS[αMDβ MDD]) had an increased αH/βSratio of 0.89 but expressed 65% βS. Expression of the human genes cured the thalassemic phenotype associated with the murine βmajor deletion. Transgenic αHβS[βMDD] mice had normal hematocrit and Hb and somewhat elevated reticulocytes (6% vs. 3% for control), whereas the mice carrying the α-globin deletion (αHβS[βMDD]) had a normal hematocrit and Hb and more elevated retieulocytes (10.3 ± 7.6% vs. 3.4 ± 1.0%). Expression of the transgene restored a normal distribution of erythrocyte densities when compared to thalassemic mice; however, the average mean corpuscular Hb concentration of αHβS[βMDD] mice increased to 35.7 g/dl (vs. control 33.7 g/dl) whereas that of αHβS[βMDD mice was further elevated to 36.3 g/dl. The intrinsic oxygen affinity was increased in transgenic mouse erythrocytes at 280 milliosmolal, and the Po2 at midsaturation of αHβS[βMDD erythrocytes was higher than that of αHβS[βMDD cells (37.4 ± 2 vs. 33.5 ± 1 mmHg). The higher values of the mean corpuscular Hb concentration and intrinsic PO2 at midsaturation, which favor in vivo sickling, may explain the slightly more severe hematological picture in αHβS[βMDD mice. We conclude that the transgenic mouse with high Hb S expression does not exhibit adult anemia but does have abnormal hematological features: increased erythrocyte density, high oxygen affinity, and reticulocytosis with increased stress retieulocytes.

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