A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder

@article{Hermans2009ACH,
  title={A compound heterozygous mutation in glycoprotein VI in a patient with a bleeding disorder},
  author={C{\'e}dric Hermans and Christine Wittevrongel and Chantal Thys and Peter A. Smethurst and Chris Van Geet and Kathleen Freson},
  journal={Journal of Thrombosis and Haemostasis},
  year={2009},
  volume={7}
}
Summary.  Background: The physiological relevance of the collagen glycoprotein VI (GPVI) receptor was known prior to its recognition as a platelet membrane receptor as several patients lacking GPVI as a consequence of autoantibody inhibition presented with a mild bleeding diathesis. Remarkably, patients with a proven GPVI gene mutation have not yet been identified. Results: In the present study, we describe a patient with a lifelong history of bleeding problems, structurally normal platelets… 
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References

SHOWING 1-10 OF 33 REFERENCES
Platelet glycoprotein VI‐related clinical defects
TLDR
Clinical profiles of patients with familial or acquired GPVI defects are reviewed, revealing the bleeding defect is often severe and associated with immune dysfunction, and expression levels of platelet GPVI may be a marker of thrombotic risk.
A patient with platelets deficient in glycoprotein VI that lack both collagen-induced aggregation and adhesion.
TLDR
The results suggest that GPVI functions as a collagen receptor, and the serum from an idiopathic thrombocytopenic purpura patient contains a specific antibody against GPVI.
A familial platelet function disorder associated with abnormal signalling through the glycoprotein VI pathway
TLDR
A familial case of abnormal platelet aggregation with dysfunctional signalling through GPVI that uniquely demonstrates divergent αIIbβ3‐activating and GPVI‐shedding pathways is reported, suggesting a signalling defect downstream of Syk.
The low-frequency allele of the platelet collagen signaling receptor glycoprotein VI is associated with reduced functional responses and expression.
TLDR
It is demonstrated for the first time that platelet function may be altered by allelic differences in GPVI, which can be specifically agonized by cross-linked collagen-related peptide (CRP-XL).
A novel platelet aggregating factor found in a patient with defective collagen-induced platelet aggregation and autoimmune thrombocytopenia.
TLDR
Results indicated that platelet aggregation by the patient's IgG was induced by the reaction of an antibody with a specific antigen on the normal platelet membrane through stimulus-response coupling.
Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily.
TLDR
The genes encoding human and mouse GPVI were identified and functional evidence demonstrating the identity of the recombinant protein with GPVI was shown, and it was demonstrated that the soluble protein blocks Cvx and collagen-induced platelet aggregation and that GPVI expression is restricted to megakaryocytes and platelets.
The TUBB 1 Q 43 P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure
TLDR
The functional consequences of the platelet Q43P 1-tubulin substitution that is frequent in the healthy population and may protect men against arterial thrombosis are presented.
The TUBB1 Q43P functional polymorphism reduces the risk of cardiovascular disease in men by modulating platelet function and structure.
TLDR
The functional consequences of the platelet Q43P beta1-tubulin substitution that is frequent in the healthy population and may protect men against arterial thrombosis are presented.
Novel Platelet Membrane Glycoprotein VI Dimorphism Is a Risk Factor for Myocardial Infarction
TLDR
The GP VI 13254CC genotype increases the risk of myocardial infarction, particularly in older individuals, and the interaction of the GPVI 13254C allele with other candidate risk alleles may accentuate this risk.
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