Monoallelic loss-of-function THPO variants cause heritable thrombocytopenia

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

doi:10.1182/bloodadvances.2019001293

Cited by 12 publications

(16 citation statements)

References 25 publications

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“…In contrast, in these cases, administering thrombopoietic agents such as romiplostim, a TPO receptor agonist (TPO-RA) does induce trilinear hematopoietic responses, remission of bleeding and infections, and transfusion independence. On the other hand, the monoallelic mutations that result in loss of function, determine decreased circulating TPO and mild thrombocytopenia with autosomal dominant inheritance [ 12 ].…”

Section: Inherited Platelet Disorders Of Particular Clinical Relevancementioning

confidence: 99%

Inherited Platelet Disorders: An Updated Overview

Palma-Barqueros

Revilla

Sánchez

et al. 2021

IJMS

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Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A genotype–phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients should be informed and comprehend the potential implications of their genetic analysis. Unlike the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized hematology service with multidisciplinary support especially for syndromic IPDs is mandatory.

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Section: Inherited Platelet Disorders Of Particular Clinical Relevancementioning

confidence: 99%

Inherited Platelet Disorders: An Updated Overview

Palma-Barqueros

Revilla

Sánchez

et al. 2021

IJMS

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“…Similarly, the epitope for neutralizing antibodies that blocked both initial binding of TPO to MPL and bioactivity mapped to the predicted site 1, whilst neutralizing antibodies that did not prevent receptor association bound to an epitope in the predicted site 2 (see below) [17]. Interestingly, levels of TPO in plasma and serum from healthy individuals [21][22][23] are more than 1000-fold below the values of K1 measured in vitro [14] and cells [11]. This suggests that under normal physiological conditions, the majority of receptors on the cell surface will not be bound to TPO.…”

Section: Thrombopoietinmentioning

confidence: 99%

“…Focusing first on TPO; (a) upregulation of THPO translation, and consequent increased serum TPO levels, resulting from point mutations within the 5ʹ-untranslated region (UTR) that remove upstream AUG codons, is a causative factor in hereditary thrombocytosis [72][73][74][75][76]; whilst (b) point mutations (i.e. R99W [22,71]) and truncations (R31* [68], R157* [71]) within the MPL-binding domain, and frameshift mutations within the C-terminal glycan domain [22] result in reduced levels of serum TPO. These latter mutations are causal factors in hereditary thrombocytopenias and bone marrow failure syndromes, and are likely due to mutant protein degradation and/or trafficking defects, potentially caused by protein misfolding.…”

Section: Pathological Tpo Signaling In Hematological Disordersmentioning

confidence: 99%

The thrombopoietin receptor: revisiting the master regulator of platelet production

Hitchcock

Hafer

Sangkhae³

et al. 2021

Platelets

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Thrombopoietin (TPO) and its receptor, MPL, are the primary regulators of platelet production and critical for hematopoietic stem cell (HSC) maintenance. Since TPO was first cloned in 1994, the physiological and pathological roles of TPO and MPL have been well characterized, culminating in the first MPL agonists being approved for the treatment of chronic immune thrombocytopenia in 2008. Dysregulation of the TPO-MPL signaling axis contributes to the pathogenesis of hematological disorders: decreased expression or function results in severe thrombocytopenia progressing to bone marrow failure, while hyperactivation of MPL signaling, either by mutations in the receptor or associated Janus kinase 2 (JAK2), results in pathological myeloproliferation. Despite its importance, it was only recently that the long-running debate over the mechanism by which TPO binding activates MPL has been resolved. This review will cover key aspects of TPO and MPL structure and function and their importance in receptor activation, discuss how these are altered in hematological disorders and consider how a greater understanding could lead to the development of better-targeted and more efficacious therapies.

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“…AR inheritance of two loss-of-function (LoF) variants in THPO causes severe thrombocytopenia and, sometimes, tri-lineage bone marrow failure, 73 whereas monoallelic LoF variants in THPO cause a mild macrothrombocytopenia only. 74,75 Another example from the BCX GWAS, relates to the GP9 variant rs5030764, which changes asparagine to serine at residue 61 of glycoprotein IX (GPIX), one of the proteins of the GPIb/IX/V platelet receptor for von Willebrand factor (VWF). In homozygosity or in compound heterozygosity with another pathogenic allele, the minor allele of rs5030764 causes Bernard-Soulier syndrome (BSS).…”

Section: The Polygenic Risk Of Macrothrombocytopeniamentioning

confidence: 99%

Advances in understanding the pathogenesis of hereditary macrothrombocytopenia

et al. 2021

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Low platelet count, or thrombocytopenia, is a common haematological abnormality, with a wide differential diagnosis, which may represent a clinically significant underlying pathology. Macrothrombocytopenia, the presence of large platelets in combination with thrombocytopenia, can be acquired or hereditary and indicative of a complex disorder. In this review, we discuss the interpretation of platelet count and volume measured by automated haematology analysers and highlight some important technical considerations relevant to the analysis of blood samples with macrothrombocytopenia. We review how large cohorts, such as the UK Biobank and INTERVAL studies, have enabled an accurate description of the distribution and co-variation of platelet parameters in adult populations. We discuss how genome-wide association studies have identified hundreds of genetic associations with platelet count and mean platelet volume, which in aggregate can explain large fractions of phenotypic variance, consistent with a complex genetic architecture and polygenic inheritance. Finally, we describe the large genetic diagnostic and discovery programmes, which, simultaneously to genome-wide association studies, have expanded the repertoire of genes and variants associated with extreme platelet phenotypes. These have advanced our understanding of the pathogenesis of hereditary macrothrombocytopenia and support a future clinical diagnostic strategy that utilises genotype alongside clinical and laboratory phenotype data.

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Monoallelic loss-of-function THPO variants cause heritable thrombocytopenia

Abstract: Key Points We report rare monoallelic variants of THPO that alter intracellular trafficking and diminish thrombopoietin secretion. Affected cases have autosomal-dominant thrombocytopenia but no other hematological features.

Cited by 12 publications

References 25 publications

Inherited Platelet Disorders: An Updated Overview

Inherited Platelet Disorders: An Updated Overview

The thrombopoietin receptor: revisiting the master regulator of platelet production

Advances in understanding the pathogenesis of hereditary macrothrombocytopenia

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