Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias

Favier, Rémi; Raslová, Hana

doi:10.1111/bjh.13478

Cited by 34 publications

(32 citation statements)

References 101 publications

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“…Classically, enlarged α‐granules are a constant feature of the Paris‐Trousseau syndrome first being seen on stained blood smears and then confirmed by EM . Paris‐Trousseau syndrome results from genetic variants and haplodeficiency of the FLI1 transcription factor, variants that were absent from our families when studied by targeted exome sequencing. For our previously studied patient with the L718del, immunogold labeling and EM clearly showed the association of P‐selectin, αIIbβ3 and fibrinogen with the giant α‐granules suggesting a normal initial granule biosynthesis .…”

Section: Discussionmentioning

confidence: 64%

Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α‐granules

et al. 2017

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Rare gain-of-function mutations within the ITGA2B or ITGB3 genes have been recognized to cause macrothrombocytopenia (MTP). Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, β3D723H. In silico analysis shows how the two mutated amino acids directly modify the salt bridge linking the intra-cytoplasmic part of αIIb to β3 of the integrin αIIbβ3. For all affected patients, the bleeding syndrome and MTP was mild to moderate. Platelet aggregation tended to be reduced but not absent. Electron microscopy associated with a morphometric analysis revealed large round platelets; a feature being the presence of abnormal large α-granules with some giant forms showing signs of fusion. Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips. Interestingly, this study revealed that in addition to the classical phenotype of patients with αIIbβ3 intracytoplasmic mutations there is an abnormal maturation of α-granules. It is now necessary to determine if this feature is a characteristic of all mutations disturbing the αIIb R995/β3 D723 salt bridge.

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Section: Discussionmentioning

confidence: 64%

Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α‐granules

et al. 2017

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“…ITs are usually asymptomatic, but some individuals may experience excessive bleeding ranging from mild to severe. Over 30 genes are shown to be involved in ITs (Favier and Raslova 2015;Levin et al 2015;Johnson et al 2016a,b;Pecci 2016). One of these, SLFN14, was discovered only very recently where Fletcher et al (2015) identified three heterozygous missense mutations in affected family members from three unrelated families, predicted to encode substitutions K218E, K219N, and V220D within an AAA domain of SLFN14.…”

Section: Introductionmentioning

confidence: 99%

Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation

Fletcher

Pisareva

Khan

et al. 2018

RNA

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Platelets are anucleate and mostly ribosome-free cells within the bloodstream, derived from megakaryocytes within bone marrow and crucial for cessation of bleeding at sites of injury. Inherited thrombocytopenias are a group of disorders characterized by a low platelet count and are frequently associated with excessive bleeding. is one of the most recently discovered genes linked to inherited thrombocytopenia where several heterozygous missense mutations in were identified to cause defective megakaryocyte maturation and platelet dysfunction. Yet, SLFN14 was recently described as a ribosome-associated protein resulting in rRNA and ribosome-bound mRNA degradation in rabbit reticulocytes. To unveil the cellular function of SLFN14 and the link between SLFN14 and thrombocytopenia, we examined SLFN14 (WT/mutants) in in vitro models. Here, we show that all variants colocalize with ribosomes and mediate rRNA endonucleolytic degradation. Compared to SLFN14 WT, expression of mutants is dramatically reduced as a result of post-translational degradation due to partial misfolding of the protein. Moreover, all SLFN14 variants tend to form oligomers. These findings could explain the dominant negative effect of heterozygous mutation on SLFN14 expression in patients' platelets. Overall, we suggest that SLFN14 could be involved in ribosome degradation during platelet formation and maturation.

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“…Several genetic variants have been associated with CMTP, of which the most frequent alter genes that encode platelet surface proteins and megakaryocyte (MK) cytoskeletal proteins. 2 …”

Section: Introductionmentioning

confidence: 99%

Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features

et al. 2017

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Congenital macrothrombocytopenia is a family of rare diseases, of which a significant fraction remains to be genetically characterized. To analyze cases of unexplained thrombocytopenia, 27 individuals from a patient cohort of the Bleeding and Thrombosis Exploration Center of the University Hospital of Marseille were recruited for a high-throughput gene sequencing study. This strategy led to the identification of two novel FLI1 variants (c.1010G>A and c.1033A>G) responsible for macrothrombocytopenia. The FLI1 variant carriers’ platelets exhibited a defect in aggregation induced by low-dose adenosine diphosphate (ADP), collagen and thrombin receptor-activating peptide (TRAP), a defect in adenosine triphosphate (ATP) secretion, a reduced mepacrine uptake and release and a reduced CD63 expression upon TRAP stimulation. Precise ultrastructural analysis of platelet content was performed using transmission electron microscopy and focused ion beam scanning electron microscopy. Remarkably, dense granules were nearly absent in the carriers’ platelets, presumably due to a biogenesis defect. Additionally, 25–29% of the platelets displayed giant α-granules, while a smaller proportion displayed vacuoles (7–9%) and autophagosome-like structures (0–3%). In vitro study of megakaryocytes derived from circulating CD34+ cells of the carriers revealed a maturation defect and reduced proplatelet formation potential. The study of the FLI1 variants revealed a significant reduction in protein nuclear accumulation and transcriptional activity properties. Intraplatelet flow cytometry efficiently detected the biomarker MYH10 in FLI1 variant carriers. Overall, this study provides new insights into the phenotype, pathophysiology and diagnosis of FLI1 variant-associated thrombocytopenia.

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Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias

Cited by 34 publications

References 101 publications

Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α‐granules

Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α‐granules

Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation

Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features

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