A new mouse model of thrombopoietin deficiency arising from a spontaneous single base pair mutation.

Han, N. S., Yvanovich, E. E., Mei, S., Roweth, H. G. ORCID: https://orcid.org/0000-0002-1100-8409, Battinelli, E. M., Sykes, D. B. and Baryawno, N. (2025) A new mouse model of thrombopoietin deficiency arising from a spontaneous single base pair mutation. Platelets, 37 (1). 2602721. ISSN 0953-7104 doi: 10.1080/09537104.2025.2602721

Abstract/Summary

Thrombopoietin (TPO) is the principal regulator of bone marrow platelet production and plays an important role in maintaining hematopoietic stem and progenitor cells. Predominantly produced in the liver, circulating TPO levels are primarily modulated through receptor-mediated clearance of TPO by target cells such as platelets. However, there is an additional component of TPO regulation at the transcriptional level, which may be affected in the setting of platelet-associated diseases. Current TPO knockout mouse models partially limit the study of transcriptional regulation because of disruption of the TPO genomic locus. Here, we describe a novel mouse model of TPO deficiency arising from a spontaneous mutation in a single base pair within exon 5 of the TPO gene. The resulting amino acid change (leucine to histidine at position 121) predicts a dramatic alteration in protein structure, ultimately resulting in a ~ 95% decrease of circulating TPO. The hematological phenotype of this new <i>C57Bl/6(IMPC)J-TPO</i>^<i>L121H</i> strain mimics that of other mouse models of TPO deficiency, but the genomic locus remains intact and therefore preserves normal TPO transcriptional regulation. We characterize the hematological phenotype of this new strain and discuss its applications as a model of transcriptional TPO regulation and clinical thrombocytopenia. Our findings highlight the theoretical possibility that TPO protein destabilizing mutations may explain rare cases of patient thrombocytopenia.

Item Type	Article
URI	https://centaur.reading.ac.uk/id/eprint/128116
Identification Number/DOI	10.1080/09537104.2025.2602721
Refereed	Yes
Divisions	No Reading authors. Back catalogue items Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	Taylor & Francis
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