An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia.

Authors: Wiestner, A  Schlemper, RJ  Van der Maas, AP  Skoda, RC 
Citation: Wiestner A, etal., Nat Genet. 1998 Jan;18(1):49-52.
Pubmed: (View Article at PubMed) PMID:9425899
DOI: Full-text: DOI:10.1038/ng0198-49

Essential thrombocythaemia (ET) is a chronic myeloproliferative syndrome due to sustained proliferation of megakaryocytes, which results in elevated numbers of circulating platelets, thrombotic or haemorrhagic episodes and occasional leukaemic transformation. The cause of ET is unknown. Hereditary thrombocythaemia (HT) with autosomal-dominant transmission has been described with manifestations similar to those of sporadic ET. As the thrombopoietin gene (THPO) encodes a lineage-restricted growth factor with profound stimulatory effects on megakaryopoiesis and platelet production, we tested the hypothesis that HT results from a mutation in the human THPO gene. In a Dutch family with eleven affected individuals, the thrombopoietin protein (TPO) concentrations in serum were consistently elevated in individuals with HT. We derived an intragenic CA marker for the human THPO gene and performed linkage analysis in fourteen informative meioses in this family. This resulted in a lod score of 3.5 at theta=0. A G-->C transversion was found in the splice donor site of intron 3 of the THPO gene in all affected family members. This mutation leads to THPO mRNAs with shortened 5'-untranslated regions (UTR) that are more efficiently translated than the normal THPO transcripts. We conclude that a splice donor mutation in THPO leads to systemic overproduction of TPO and causes thrombocythaemia.

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CRRD ID: 1580083
Created: 2006-06-22
Species: All species
Last Modified: 2006-06-22
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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.