Lessons in platelet production from inherited thrombocytopenias

Pecci, Alessandro; Balduini, Carlo L.

doi:10.1111/bjh.12752

Cited by 36 publications

(33 citation statements)

References 112 publications

(158 reference statements)

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“…At the platelet level, macrocytosis is observed with or without thrombocytopenia. 8,9 These observations are consistent with data obtained in a mouse model lacking filamin A in the platelet lineage, which is characterized by severe macrothrombocytopenia and decreased expression of the GPIb-IX complex on the platelet surface. 47 Thrombocytopenia results from both rapid clearance of the platelets appearing most vulnerable and ineffective platelet production.…”

Section: Fnla-related Thrombocytopeniasupporting

confidence: 85%

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The contribution of mouse models to the understanding of constitutional thrombocytopenia

et al. 2016

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Article summary• Constitutional thrombocytopenias of hereditary origin have long been poorly studied due to the difficulties of obtaining invasive marrow samples.• Genetic engineering has allowed the generation of numerous mouse models for all these pathologies, providing invaluable information to understanding these diseases and serving as preclinical models to test new therapies.Constitutional thrombocytopenias result from genetic mutations affecting platelet production. These rare diseases are still underdiagnosed, especially in adults, because they remain little-known and have a highly variable expression. Autoimmune thrombocytopenia is still often wrongly diagnosed, thereby leading to the inadequate management of patients, with occasionally inappropriate splenectomy. The diagnosis of congenital thrombocytopenia relies on cytological and functional platelet analyses performed almost exclusively in specialized laboratories. Furthermore, about 50% of thrombocytopenias, associated or not with a thrombopathy, still remain of unknown origin. 1 In cases where platelet studies orient the diagnosis to a known disease, the detection of mutations in the suspected genes can C onstitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia.The contribution of mouse models to the understanding of constitutional thrombocytope...

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Section: Fnla-related Thrombocytopeniasupporting

confidence: 85%

“…We will then describe the various constitutional thrombocytopenias where the contribution of animal models has been essential for their elucidation and/or treatment. For a more detailed description of the human pathologies, the reader may refer to three excellent reviews [7][8][9] and the OMIM database (input numbers in Table 1). …”

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confidence: 99%

The contribution of mouse models to the understanding of constitutional thrombocytopenia

et al. 2016

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“…4 Altered regulation of platelet formation is a feature of several human hematopoietic disorders, including macrothrombocytopenia (MTP), in which circulating platelets are enlarged and reduced in number, sometimes resulting in abnormal bleeding. 5,6 MTP has been associated with pathogenic variants in genes that regulate MK maturation (GATA1, GFI1B, and NBEAL2) or that encode platelet surface proteins (GP1BA, GP1BB, GP9, ITGA2B, and ITGB3; reviewed in Pecci and Balduini 5 ). However, a prevalent subgroup of MTP arises from variants in ACTN1, 7 FLNA, 8 MYH9, 9,10 TUBB1, 11 and PRKACG 12 that encode MK cytoskeletal proteins or interactors.…”

Section: Introductionmentioning

confidence: 99%

A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

Stritt

Nurden

Turro

et al. 2016

Blood

134

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Key Points• A gain-of-function variant in DIAPH1 causes macrothrombocytopenia and hearing loss and extends the spectrum of DIAPH1-related disease.• Our findings of altered megakaryopoiesis and platelet cytoskeletal regulation highlight a critical role for DIAPH1 in platelet formation.Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease andprovides new insight into the autoregulation of DIAPH1 activity.

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“…Instead, the data support a model (depicted in Figure 6 of Padrón-Barthe et al 1 ) where the precursors for primitive blood and yolk sac endothelium are already specified before gastrulation, 3,4 and colonize the yolk sac sequentially with the endothelial-fated lineage encircling the blood-fated cells. 10 The authors propose that part of the labeled yolk sac endothelium represents the hemogenic endothelium that contributes to blood through an endothelial to hematopoietic transition.…”

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confidence: 48%