Monoallelic loss-of-function THPO variants cause heritable thrombocytopenia

Naomi Cornish, M Riyaad Aungraheeta, Lucy FitzGibbon, Kate Burley, Dominic Alibhai, Janine Collins, Daniel Greene, Kate Downes, NIHR BioResource, Sarah K Westbury, Ernest Turro, Andrew D Mumford

Research output: Contribution to journalArticle (Academic Journal)peer-review

27 Downloads (Pure)


Thrombopoietin (TPO) is a lineage-specific cytokine that is synthesized predominantly in hepatocytes and is an essential regulator of self-renewal of hematopoietic stem cells and their differentiation into platelet-forming megakaryocytes. The major TPO isoform is a 353-aa peptide containing a highly glycosylated C-terminal domain and an amino-terminal receptor binding domain (RBD) that mediates interaction with the TPO receptor (c-mpl) on hematopoietic cells. TPO is encoded by the THPO gene, which maps to 3q27.1 and contains up to 6 coding exons.

Increased TPO production caused by gain-of-function THPO variants results in the myeloproliferative disorder thrombocythemia-1 (Online Mendelian Inheritance in Man #187950), in which the circulating platelet count is elevated, sometimes causing bleeding or thrombosis. In contrast, biallelic loss-of-function THPO variants result in a severe reduction in the platelet count and multilineage bone marrow failure. Here, we present genetic and functional evidence that monoallelic loss-of-function THPO variants also result in reduced platelet count but do not affect other circulating blood cells.
Original languageEnglish
Pages (from-to)920-924
Number of pages5
JournalBlood Advances
Issue number5
Early online date9 Mar 2020
Publication statusPublished - 10 Mar 2020

Fingerprint Dive into the research topics of 'Monoallelic loss-of-function THPO variants cause heritable thrombocytopenia'. Together they form a unique fingerprint.

Cite this