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Blood, 15 December 2005, Vol. 106, No. 13, pp. 4102-4113.
Prepublished online as a Blood First Edition Paper on August 18, 2005; DOI 10.1182/blood-2005-03-1060.
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Submitted March 15, 2005
Accepted August 10, 2005
Variegation of the phenotype induced by the GATA-1low mutation in mice of different genetic background
Fabrizio Martelli, Barbara Ghinassi, Barbara Panetta, Elena Alfani, Valentina Gatta, Alessandro Pancrazzi, Costanza Bogani, Alessandro M Vannucchi, Francesco Paoletti, Giovanni Migliaccio, and Anna Rita Migliaccio*
Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanita, Rome, Italy
Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanita, Rome, Italy; Biomorphology, University G. D'Annunzio, Chieti, Italy
Cell Biology and Neurosciences, Istituto Superiore Sanita, Rome, Italy
Medical Genetics, University G. D' Annunzio, Chieti, Italy
Hematology, Azienda Ospedaliera Careggi, Florence, Italy
Oncology and Experimental Pathology, University of Florence, Florence, Italy
* Corresponding author; email: migliar{at}iss.it.
All the mice harboring the X-linked GATA-1low mutation in a predominantly CD1 background are born anemic and thrombocytopenic. They recover from anemia at 1-month of age but remain thrombocytopenic all their life and develop myelofibrosis, a syndrome similar to human idiopathic myelofibrosis, at 12-months. The effects of the genetic background on the myelofibrosis developed by GATA-1low mice was assessed by introducing the mutation, by standard genetic approaches, in the C57BL/6 and DBA/2 backgrounds and by analyzing the phenotype of the different mutants at 12-13- (by histology) and 15-18- (by cytofluorimetry) months of age. Although all the GATA-1low mice developed fibrosis at 12-13-months, variegations were observed in the severity of the phenotype expressed by mutants of different backgrounds. In predominantly C57BL/6 mice, the mutation was no longer inherited in a mendelian fashion and fibrosis was associated with massive osteosclerosis. Instead, DBA/2 mutants, although severely anemic, expressed limited fibrosis and osteosclerosis and did not present tear-drop poikilocytes in the blood and extramedullary hemopoiesis in the liver up to 20-months of age. We propose that the variegation in myelofibrosis expressed by GATA-1low mutants in different strains might represent a model for the variability of the clinical picture of the human disease.
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