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

Abstract

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.

The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production

“…Investigation of the TPO locus in these families has revealed a relatively new form of disease, that of mRNA translation e ciency (Cazzola and Skoda, 2000). To understand the basis of these disorders, one must appreciate that TPO mRNA is very ine ciently translated into protein, due to the presence of several short open reading frames (ORFs) upstream of the usual site of translation initiation (Wiestner et al, 1998). In four separate families, four distinct mutations of the gene have been described, all of which lead to greatly enhanced translation e ciency of TPO mRNA.…”

Multivariate QTL linkage analysis suggests a QTL for platelet count on chromosome 19q

“…While mutations in the genes for thrombopoietin and the thrombopoietin receptor are known to produce clinical pathology (eg Congenital Amegakaryocytic Thrombocytopenia, Essential Thrombocythemia), the present results suggest that other regions of the genome may be more important in determining variation in platelet count amongst healthy adolescent twins. 37,38 In most positions along the genome the multivariate analyses (ie Multivariate test I and Multivariate test II) did not increase the power to detect linkage relative to the univariate results. This was perhaps surprising given that several theoretical papers have documented a clear advantage of multivariate approaches in the power to detect QTLs.…”

An 8.4‐Mb 3q26.33‐3q28 microdeletion in a patient with blepharophimosis–intellectual disability syndrome and a review of the literature

“…Indeed, at least half of the 3q26.33‐3q27.2 microdeletion cases have thrombocytopenia (Table 1), and mutations in THPO gene causing improved translational efficiency have been shown to be responsible for hereditary autosomal‐dominant thrombocythemia 17, 18. However, LAMP3 gene is not located in the SRO and therefore, is probably not causative for the common phenotype as was suggested before.…”