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Dominant negative Gfi1b mutations cause moderate thrombocytopenia and an impaired stress thrombopoiesis associated with mild erythropoietic abnormalities in mice by Hugues Beauchemin; Peiman Shooshtharizadeh; Jordan Pinder; Graham Dellaire; Tarik Möröy is a Medicine article available to read on EtoBox.

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__GFI1B__-related thrombocytopenia (__GFI1B__-RT) is a rare bleeding disorder mainly caused by the presence of truncated GFI1B proteins with dominant-negative properties. The disease is characterized by low platelet counts, the presence of abnormal platelets, a megakaryocytic expansion, and mild erythroid defects. However, there are no animal models that faithfully reproduce the __GFI1B__-RT phenotype observed in patients. We had previously generated mice with floxed Gfi1b alleles that can be eliminated by Cre recombinase, but those animals developed a much more severe phenotype than __GFI1B__-RT patients and were of limited interest in assessing the disease. Using CRISPR/Cas9 technology, we have now established three independent mouse lines that carry mutated __Gfi1b__ alleles producing proteins lacking DNA binding zinc fingers and thereby acting in a dominant negative (DN) manner. Mice heterozygous for these Gfi1b-DN alleles show reduced platelet counts and an expansion of megakaryocytes similar to features of human __GFI1B__-RT but lacking the distinctively large agranular platelets. In addition, __Gfi1b__-DN mice exhibit an expansion of erythroid precursors indicative of a mild

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Author

Hugues Beauchemin; Peiman Shooshtharizadeh; Jordan Pinder; Graham Dellaire; Tarik Möröy

Published

2019

Language

EN

Field

Medicine (Health Sciences)