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

TH Open ◽  
2020 ◽  
Vol 04 (04) ◽  
pp. e413-e416
Author(s):  
Julia Körholz ◽  
Nadja Lucas ◽  
Franziska Boiti ◽  
Karina Althaus ◽  
Oliver Tiebel ◽  
...  
Keyword(s):  
Platelet Function ◽  
Adenosine Diphosphate ◽  
Severe Bleeding ◽  
Bleeding Diathesis ◽  
Nucleotide Exchange ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Whole Exome ◽  
Platelet Function Disorders ◽  
Diagnostic Work

AbstractNext-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.

Evaluation of the Gene Encoding Calcium Diacylglycerol Guanine Nucleotide Exchange Factor I (CalDAG-GEFI) in Human Patients with Congenital Qualitative Platelet Disorders.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 5078-5078
Author(s):  
John Puetz ◽  
Mary Boudreaux
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Guanine Nucleotide ◽  
Nucleotide Exchange ◽  
Factor I ◽  
Normal Platelet ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Platelet Function Disorders ◽  
Mucocutaneous Bleeding

Abstract Abstract 5078 Normal platelet function is dependent on an orchestrated series of interactions resulting in primary hemostasis. Dysfunction in any step of platelet activation and aggregation results in abnormal platelet function and abnormal mucocutaneous bleeding. Defects in agonist/receptor interactions, membrane phospholipid and cytoskeleton structure, signal transduction, storage pool content and release have all been described. While some congenital qualitative platelet function disorders such as Bernard-Soulier syndrome or Glanzmann thrombasthenia are well characterized at the molecular and genetic level, the majority of congenital platelet function disorders are not. Recently, insights into the molecular and genetic causes of platelet signal transduction and secretion pathway disorders have been found in animals. Dogs and cattle with recurrent abnormal mucocutaneous bleeding symptoms and abnormal in vitro platelet aggregation have been found to be caused by a mutation in the calcium-diacylglycerol guanine nucleotide exchange factor I (CalDAG-GEFI) gene. Genetic ablation of CalDAG-GEFI in mice has resulted in abnormal platelet function and bleeding. Polymorphisms in the human CalDAG-GEFI gene have been linked to Kindlin-3/ FERMT3 mutations resulting in a leukocyte adhesions defect associated with platelet dysfunction (LAD-III or LAD-1/variant syndrome). To date, mutations in the CalDAG-GEFI gene in humans associated with abnormal platelet function and bleeding have not been described. To determine if mutations in the human CalDAG-GEFI gene are associated with abnormal mucocutaneous bleeding and platelet aggregation dysfunction, we have begun sequencing the CalDAG-GEFI gene in human patients with a congenital qualitative platelet function disorder of unknown etiology. As control groups, we will also evaluate the CalDAG-GEFI gene sequence of unaffected family members and unrelated blood donors known to have normal platelet aggregation. Preliminary results of our analysis will be presented. Disclosures No relevant conflicts of interest to declare.

scholarly journals Leukaemia-associated Rho guanine nucleotide exchange factor (LARG) plays an agonist specific role in platelet function through RhoA activation

2016 ◽  
Vol 116 (09) ◽  
pp. 506-516 ◽  
Author(s):  
Siying Zou ◽  
Alexandra M. Teixeira ◽  
Mingzhu Yin ◽  
Yaozu Xiang ◽  
Juliana Xavier-Ferruccio ◽  
...  
Keyword(s):  
Platelet Function ◽  
Thrombus Formation ◽  
Human Platelets ◽  
Specific Role ◽  
Nucleotide Exchange ◽  
Rhoa Activation ◽  
Guanine Nucleotide Exchange ◽  
Nucleotide Exchange Factor ◽  
Internal Bleeding

SummaryLeukemia-Associated RhoGEF (LARG) is highly expressed in platelets, which are essential for maintaining normal haemostasis. We studied the function of LARG in murine and human megakaryocytes and platelets with Larg knockout (KO), shRNA-mediated knockdown and small molecule-mediated inhibition. We found that LARG is important for human, but not murine, megakaryocyte maturation. Larg KO mice exhibit macrothrombocytopenia, internal bleeding in the ovaries and prolonged bleeding times. KO platelets have impaired aggregation, α-granule release and integrin α2bβ3 activation in response to thrombin and thromboxane, but not to ADP. The same agonist-specific reductions in platelet aggregation occur in human platelets treated with a LARG inhibitor. Larg KO platelets have reduced RhoA activation and myosin light chain phosphorylation, suggesting that Larg plays an agonist-specific role in platelet signal transduction. Using two different in vivo assays, Larg KO mice are protected from in vivo thrombus formation. Together, these results establish that LARG regulates human megakaryocyte maturation, and is critical for platelet function in both humans and mice.Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals A role of histone H3 lysine 4 methyltransferase components in endosomal trafficking

2009 ◽  
Vol 186 (3) ◽  
pp. 343-353 ◽  
Author(s):  
Zhuojin Xu ◽  
Qiang Gong ◽  
Bin Xia ◽  
Benjamin Groves ◽  
Marc Zimmermann ◽  
...  
Keyword(s):  
Histone H3 ◽  
Adenosine Diphosphate ◽  
Endosomal Trafficking ◽  
Nucleotide Exchange ◽  
Recycling Endosomes ◽  
Guanine Nucleotide Exchange ◽  
Histone Lysine Methyltransferase ◽  
Nucleotide Exchange Factor ◽  
Cargo Proteins ◽  
Lysine Methyltransferase

Histone lysine methyltransferase complexes are essential for chromatin organization and gene regulation. Whether any of this machinery functions in membrane traffic is unknown. In this study, we report that mammal Dpy-30 (mDpy-30), a subunit of several histone H3 lysine 4 (H3K4) methyltransferase (H3K4MT) complexes, resides in the nucleus and at the trans-Golgi network (TGN). The TGN targeting of mDpy-30 is mediated by BIG1, a TGN-localized guanine nucleotide exchange factor for adenosine diphosphate ribosylation factor GTPases. Altering mDpy-30 levels changes the distribution of cation-independent mannose 6-phosphate receptor (CIMPR) without affecting that of TGN46 or transferrin receptor. Our experiments also indicate that mDpy-30 functions in the endosome to TGN transport of CIMPR and that its knockdown results in the enrichment of internalized CIMPR and recycling endosomes near cell protrusions. Much like mDpy-30 depletion, the knockdown of Ash2L or RbBP5, two other H3K4MT subunits, leads to a similar redistribution of CIMPR. Collectively, these results suggest that mDpy-30 and probably H3K4MT play a role in the endosomal transport of specific cargo proteins.

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