RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology

Canault, Matthias; Alessi, Marie‐Christine

doi:10.3390/ijms21031075

Cited by 23 publications

(29 citation statements)

References 101 publications

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“…18,19 From 2001, the year in which P2RY12 was first characterized, 10 newly identified genes include FERMT3, ANO6, RASGRP2 and EPHB2 thereby expanding the gene repertoire for IPD. 25,26,33,34,36,43 The development of next-generation sequencing platforms targeting IPD genes, 6,88 together with widening access to whole exome sequencing, 4,7,8 and now whole genome sequencing, 9 has both increased the number of patients with a genetic diagnosis and the speed at which this is performed. The multiplication of data has underlined the great diversity of variants responsible for gene dysfunction, the rarity of hot-spot mutations, the frequency of compound heterozygosity within the same gene (limiting the notion of consanguinity for recessive diseases); and raised the likelihood of additive effects of heterozygous variants on different genes modulating the phenotype.…”

Section: Discussionmentioning

confidence: 99%

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

et al. 2020

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Inherited platelet disorders resulting from platelet function defects and a normal platelet count cause a moderate or severe bleeding diathesis. Since the description of Glanzmann thrombasthenia resulting from defects of ITGA2B and ITGB3, new inherited platelet disorders have been discovered, facilitated by the use of high throughput sequencing and genomic analyses. Defects of RASGRP2 and FERMT3 responsible for severe bleeding syndromes and integrin activation have illustrated the critical role of signaling molecules. Important are mutations of P2RY12 encoding the major ADP receptor causal for an inherited platelet disorder with inheritance characteristics that depend on the variant identified. Interestingly, variants of GP6 encoding the major subunit of the collagen receptor GPVI/FcRγ associate only with mild bleeding. The numbers of genes involved in dense granule defects including Hermansky-Pudlak and Chediak Higashi syndromes continue to progress and are updated. The ANO6 gene encoding a Ca2+-activated ion channel required for phospholipid scrambling is responsible for the rare Scott syndrome and decreased procoagulant activity. A novel EPHB2 defect in a familial bleeding syndrome demonstrates a role for this tyrosine kinase receptor independent of the classical model of its interaction with ephrins. Such advances highlight the large diversity of variants affecting platelet function but not their production, despite the difficulties in establishing a clear phenotype when few families are affected. They have provided insights into essential pathways of platelet function and have been at the origin of new and improved therapies for ischemic disease. Nevertheless, many patients remain without a diagnosis and requiring new strategies that are now discussed.

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Section: Discussionmentioning

confidence: 99%

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

et al. 2020

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“…CalDAG-GEFI deficiency primarily affects platelet activation induced by low-dose agonist activation involving the first wave of activation. 21 This type of response may also correspond to abnormalities in the amplification pathway mediated by ADP. Reduced response to ADP even at high concentrations (100 μM) has been observed in severe homozygous P2Y12 deficiency [22][23][24][25] (►Table 1).…”

Section: Light Transmission Platelet Aggregationmentioning

confidence: 99%

Laboratory Techniques Used to Diagnose Constitutional Platelet Dysfunction

2020

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Platelets play a major role in primary hemostasis, where activated platelets form plugs to stop hemorrhaging in response to vessel injuries. Defects in any step of the platelet activation process can cause a variety of platelet dysfunction conditions associated with bleeding. To make an accurate diagnosis, constitutional platelet dysfunction (CPDF) should be considered once von Willebrand disease and drug intake are ruled out. CPDF may be associated with thrombocytopenia or a genetic syndrome. CPDF diagnosis is complex, as no single test enables the analysis of all aspects of platelet function. Furthermore, the available tests lack standardization, and repeat tests must be performed in specialized laboratories especially for mild and moderate forms of the disease. In this review, we provide an overview of the laboratory tests used to diagnose CPDF, with a focus on light transmission platelet aggregation (LTA), flow cytometry (FC), and granules assessment. Global tests, mainly represented by LTA, are often initially performed to investigate the consequences of platelet activation on platelet aggregation in a single step. Global test results should be confirmed by additional analytical tests. FC represents an accurate, simple, and reliable test to analyze abnormalities in platelet receptors, and granule content and release. This technique may also be used to investigate platelet function by comparing resting- and activated-state platelet populations. Assessment of granule content and release also requires additional specialized analytical tests. High-throughput sequencing has become increasingly useful to diagnose CPDF. Advanced tests or external research laboratory techniques may also be beneficial in some cases.

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“…The associated bleeding disorder has been referred to as bleeding disorder platelet-type 18 (BDPLT18). 3 Altogether, more than 20 human disease-causing genetic RASGRP2 variants have been reported up to today. 3,4 In the first description of mutant RasGRP2, Canault et al reported an abolished Rap1 activation in patient platelets upon stimulation, indicating defective platelet aggregation.…”

Section: Introductionmentioning

confidence: 99%

“…3 Altogether, more than 20 human disease-causing genetic RASGRP2 variants have been reported up to today. 3,4 In the first description of mutant RasGRP2, Canault et al reported an abolished Rap1 activation in patient platelets upon stimulation, indicating defective platelet aggregation. 5 In contrast, other platelet activation mechanisms including protein kinase C and adenosine diphosphate (ADP) dependent pathways were not affected by RASGRP2 mutations.…”

Section: Introductionmentioning

confidence: 99%

“…In general, glycoprotein receptor expression is usually not impaired, whereas thrombus formation and platelet spreading have been demonstrated to be impaired in murine RasGRP2 deficiency. 3,5,6 Consequently, typical findings of platelet aggregation testing in patients include an absent or reduced aggregation potential in response to low concentrations of the platelet agonists ADP and collagen. 7 Clinically, affected individuals exhibit a severe bleeding tendency, especially at Keywords ► bleeding diathesis ► platelet dysfunction ► RASGRP2…”

Section: Introductionmentioning

confidence: 99%

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Severe Bleeding Diathesis in Siblings with Platelet Dysfunction due to a Novel Nonsense RASGRP2 Mutation

Körholz

Lucas

Boiti

et al. 2020

TH Open

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Next-generation sequencing is increasingly applied during the diagnostic work-up of patients with bleeding diathesis and has facilitated the diagnosis of rare bleeding disorders such as inherited platelet function disorders. Mutations in RAS guanyl releasing protein 2 (RasGRP2), also known as calcium- and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), underlie a recently described platelet signal transduction abnormality. Here we present the case of a consanguineous family originating from Afghanistan with two siblings affected by recurrent severe mucocutaneous bleedings. Platelet function testing demonstrated a marked reduction of aggregation induced by collagen and adenosine diphosphate. Whole exome sequencing revealed a novel homozygous nonsense RASGRP2 mutation segregating with the bleeding disorder in the family.

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RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology

Cited by 23 publications

References 101 publications

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

Laboratory Techniques Used to Diagnose Constitutional Platelet Dysfunction

Severe Bleeding Diathesis in Siblings with Platelet Dysfunction due to a Novel Nonsense RASGRP2 Mutation

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