Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding

Westbury, Sarah K; Canault, Matthias; Greene, Daniel; Bermejo, Emilse; Hanlon, Katharine; Lambert, Michele P.; Millar, Carolyn M.; Nurden, Paquita; Obaji, Samya; Revel‐Vilk, Shoshana; Geet, Chris Van; Downes, Kate; Papadia, Sofia; Tuna, Salih; Watt, Christopher D.; Freson, Kathleen; Laffan, Michael; Ouwehand, Willem H.; Alessi, Marie‐Christine; Turro, Ernest; Mumford, Andrew D

doi:10.1182/blood-2017-03-776773

Cited by 39 publications

(44 citation statements)

References 24 publications

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“…Data collection, human phenotype ontology (HPO) coding, and high-throughput sequencing were performed as previously reported. 18 Splice site, frameshift, stop-gain/ loss or start-loss variants were analyzed further if they were less frequent than 1 in 10 000 in the Exome Aggregation Consortium database and 1 in 100 in our in-house database. Candidate genes for BPD were identified by phenotype similarity regression 19 to allow for the high degree of phenotypic and genetic heterogeneity among the BPD cases.…”

Section: Recruitment Of Cases and Genetic Analysismentioning

confidence: 99%

“…(A) Each BPD index case was coded using HPO terms relating to hematologic features and to phenotypes in other organ systems and underwent high-throughput sequencing. 18 Candidate genes for BPD were identified by similarity regression in which "baseline" and "alternate" statistical models are compared for every gene. 19 Under the baseline model, all cases are assumed to have the same log odds of carrying a rare variant.…”

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confidence: 99%

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

Stritt

Nurden

Turro

et al. 2016

Blood

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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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Section: Recruitment Of Cases and Genetic Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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

Stritt

Nurden

Turro

et al. 2016

Blood

Self Cite

134

150

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“…Given these numbers, it can be concluded that (1) only minimal changes in cytosolic calcium are required to mount a robust CalDAG-GEFI response, and (2) that some CalDAG-GEFI protein exists in an active conformation even in circulating, quiescent platelets. Consistent with these conclusions, complete CalDAG-GEFI deficiency is ill tolerated as it causes moderate to severe bleeding in humans and mice[51,53–55,58–60]. At the same time, CalDAG-GEFI/RAP1 signaling has to be restrained by RASA3 in circulating platelets to avoid severe thrombocytopenia and blood-lymphatic mixing in the developing embryo.…”

Section: Classical Hemostasis – Balancing Platelet Adhesiveness In CImentioning

confidence: 85%

“…The result is a near-immediate integration of second messenger generation and integrin activation. Lack of CalDAG-GEFI leads to impaired thrombus formation and bleeding[51,53–55,57–60]. …”

Section: Classical Hemostasis – Balancing Platelet Adhesiveness In CImentioning

confidence: 99%

Platelets at the vascular interface

Bergmeier

Stefanini

2018

Research and Practice in Thrombosis and Haemostasis

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In this brief review paper, we will summarize the State-of-the-Art on how platelet reactivity is regulated in circulation and at sites of vascular injury. Our review discusses recent and ongoing work, presented at this year’s International Society on Thrombosis and Haemostasis (ISTH) meeting, on the role of platelets in (1) classical hemostasis at sites of mechanical injury, and (2) the maintenance of vascular integrity at sites of inflammation.

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“…Our studies have important clinical implications. Mutations in RasGRP2, the gene encoding CDGI, have recently been recognized as a new class of platelet function disorder . Although most variants lead to impaired expression of CDGI in patient platelets, some impair the function of an expressed protein.…”

Section: Discussionmentioning

confidence: 99%

Subcellular localization of Rap1 GTPase activator CalDAG‐GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides

Sarker

Goliaei

Golesi

et al. 2020

Journal of Thrombosis and Haemostasis

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Background The small GTPase Rap1 and its guanine nucleotide exchange factor, CalDAG‐GEFI (CDGI), are critical for platelet function and hemostatic plug formation. CDGI function is regulated by a calcium binding EF hand regulatory domain and an atypical C1 domain with unknown function. Objective Here, we investigated whether the C1 domain controls CDGI subcellular localization, both in vitro and in vivo. Methods CDGI interaction with phosphoinositides was studied by lipid co‐sedimentation assays and molecular dynamics simulations. Cellular localization of CDGI was studied in heterologous cells by immunofluorescence and subcellular fractionation assays. Results Lipid co‐sedimentation studies demonstrated that the CDGI C1 domain associates with membranes through exclusive recognition of phosphoinositides, phosphatidylinositol (4,5)‐biphosphate (PIP2) and phosphatidylinositol (3,4,5)‐triphosphate (PIP3). Molecular dynamics simulations identified a phospholipid recognition motif consisting of residues exclusive to the CDGI C1 domain. Mutation of those residues abolished co‐sedimentation of the C1 domain with lipid vesicles and impaired membrane localization of CDGI in heterologous cells. Conclusion Our studies identify a novel interaction between an atypical C1 domain and phosphatidylinositol (4,5)‐biphosphate and phosphatidylinositol (3,4,5)‐triphosphate in cellular membranes, which is critical for Rap1 signaling in health and disease.

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Expanded repertoire of RASGRP2 variants responsible for platelet dysfunction and severe bleeding

Abstract: Key Points Eleven pedigrees were identified with biallelic pathogenic variants in RASGPR2, which encodes platelet CalDAG-GEFI. CalDAG-GEFI deficiency is a severe, recessive, nonsyndromic platelet function disorder with defective aggregation to multiple agonists.

Cited by 39 publications

References 24 publications

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

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

Platelets at the vascular interface

Subcellular localization of Rap1 GTPase activator CalDAG‐GEFI is orchestrated by interaction of its atypical C1 domain with membrane phosphoinositides

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