RGD Reference Report - Heterozygous ITGA2B R995W mutation inducing constitutive activation of the alphaIIbbeta3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia.

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Heterozygous ITGA2B R995W mutation inducing constitutive activation of the alphaIIbbeta3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia.
Authors:	Kunishima, S Kashiwagi, H Otsu, M Takayama, N Eto, K Onodera, M Miyajima, Y Takamatsu, Y Suzumiya, J Matsubara, K Tomiyama, Y Saito, H
Citation:	Kunishima S, etal., Blood. 2011 May 19;117(20):5479-84. doi: 10.1182/blood-2010-12-323691. Epub 2011 Mar 31.
RGD ID:	10755467
Pubmed:	PMID:21454453 (View Abstract at PubMed)
DOI:	DOI:10.1182/blood-2010-12-323691 (Journal Full-text)
Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. alphaIIbbeta3 has not been implicated in these conditions. We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families. The surface expression of platelet alphaIIbbeta3 was decreased to 50% to 70% of control. There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression. The activation state of alphaIIbbeta3 in 293T cells was higher for alphaIIb-W995 than for beta3-H723 but was weaker than for beta3-N562. FAK was spontaneously phosphorylated in alphaIIb-W995/beta3-transfected 293T cells. These results indicate that alphaIIb-W995/beta3 has a constitutive, activated conformation but does not induce platelet activation. alphaIIb-W995/beta3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions. The increased size and decreased number of proplatelet tips in alphaIIb-W995/beta3-transduced mouse fetal liver-derived megakaryocytes indicate defective pro-platelet formation. We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
ITGA2B	Human	thrombocytopenia		IAGP		DNA:missense mutation: :p.R995W (human)	RGD
Itga2b	Mouse	thrombocytopenia		ISO	ITGA2B (Homo sapiens)	DNA:missense mutation: :p.R995W (human)	RGD
Itga2b	Rat	thrombocytopenia		ISO	ITGA2B (Homo sapiens)	DNA:missense mutation: :p.R995W (human)	RGD

Objects Annotated

Genes (Rattus norvegicus)

Itga2b (integrin subunit alpha 2b)

Genes (Mus musculus)

Itga2b (integrin alpha 2b)

Genes (Homo sapiens)

ITGA2B (integrin subunit alpha 2b)

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Heterozygous ITGA2B R995W mutation inducing constitutive activation of the alphaIIbbeta3 receptor affects proplatelet formation and causes congenital macrothrombocytopenia.