The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel.

Newman, Peter J.; Seligsohn, Uri; Lyman, Suzanne; Coller, Barry S.

doi:10.1073/pnas.88.8.3160

Cited by 164 publications

(117 citation statements)

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“…Platelets of Iraqi-Jewish patients with an ITGB3 mutation (c.2031-2041del/premature termination) lacked both integrins but contained 5-fold more vitronectin while still not storing Fg. 10,23,24 It was proposed that vitronectin, synthesized in MKs, is normally transported out of the cells by ␣v␤3 largely localized to small vesicular structures in platelets. 25 Nevertheless, clinically, the Iraqi-Jewish and Arab patients are indistinguishable.…”

Section: Integrin ␣V␤3 In Thrombastheniamentioning

confidence: 99%

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Nurden

Fiore

Pillois

2011

Blood

202

269

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Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetypeinherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, ␣IIb␤3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for ␤3 has a wide tissue distribution when present as ␣v␤3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of ␤3-deficiency or nonfunction are being increasingly described. (Blood. 2011;118(23):5996-6005) IntroductionGlanzmann thrombasthenia (GT) is the most frequently encountered inherited disorder of platelet function. [1][2][3] Patients have a lifelong hemorrhagic syndrome typically characterized by episodes of spontaneous mucocutaneous bleeding. Platelets fail to aggregate in response to stimuli because they lack or have nonfunctional ␣IIb␤3 integrin (formerly known as GPIIb-IIIa). Resting normal platelets are suspected to have ␣IIb␤3 in a bent conformation; when platelets are stimulated, the integrin straightens in parallel to the exposure of determinants essential for the binding of fibrinogen (Fg) or other soluble adhesive proteins. 3,4 The latter assure aggregation by cross-linking adjacent platelets, a process that cannot occur in GT. Elucidation of this pathway led to the development of integrin-blocking drugs that are strong inhibitors of arterial thrombosis, thereby increasing interest in the clinical manifestations of GT. 3,4 Platelet ␣IIb␤3 also transmits the forces generated by intracellular cytoskeletal proteins during clot contraction and platelet spreading, processes that also fail in patients lacking adequate amounts of functional integrin.Although the GT phenotype is well defined, bleeding severity differs considerably between affected persons, even within the same family or ethnic group. 1,2 In this review, we discuss phenotypic variability, present variant types, and identify possible additional effects associated with ␤3 deletion, for although ␣IIb is largely restricted to the megakaryocyte (MK) lineage, ␤3 is much more widespread in its tissue distribution occurring as ␣v␤3, the vitronectin receptor. 5,6 Data for patients will be compared with those obtained for...

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Section: Integrin ␣V␤3 In Thrombastheniamentioning

confidence: 99%

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Nurden

Fiore

Pillois

2011

Blood

202

269

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“…Glanzmann thrombasthenia (GT), an inherited disorder of platelet function, is extremely rare except in populations (such as Iranians, Southern Indians, and Iraqi Jews) where consanguineous marriages are common [1,2]. We carried out a retrospective descriptive study to define age at first observation, clinical manifestations, platelet and leukocyte count, and hemoglobin levels in GT patients referred to and diagnosed at our institution in Iran from 1969 to 2001.…”

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confidence: 99%

Presentation and pattern of symptoms in 382 patients with Glanzmann thrombasthenia in Iran

et al. 2004

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Glanzmann thrombasthenia (GT) is a rare autosomal recessive disease characterized by prolonged bleeding time with normal platelet count and morphology. It is caused by the quantitative or qualitative deficiency of the platelet glycoprotein IIb-IIIa. In 382 Iranian patients with GT diagnosed at a single center during the period 1969-2001, consanguinity between parents was 86.6%, in accord with the high frequency of intrafamilial marriages in Iran. Almost all patients had had abnormal mucocutaneous bleeding (epistaxis and gum bleeding); at follow-up, 4/5 of the patients had been transfused at least once to control hemorrhagic episodes. As expected, almost all the patients had a normal platelet count while the leukocyte count was increased in 19.3%. Among women, an unexpected low rate of pregnancies was observed. Am.

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“…Numerous genetic defects have been previously described for type I GT in human beings, 1,7,8,10,11,15,20,[24][25][26][27]35,37,42,[44][45][46][47]49,51 but this is the first molecular genetic defect described for canine type I GT. Because the nucleotide sequences of canine ␣ IIb (GenBank accession no.…”

Section: Discussionmentioning

confidence: 99%

Two Genetic Defects in α_IIb Are Associated with Type I Glanzmann's Thrombasthenia in a Great Pyrenees Dog: A 14-base Insertion in Exon 13 and a Splicing Defect of Intron 13

2000

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Abstract. Glannzmann's thrombasthenia (GT) is an autosomal recessive bleeding disorder caused by qualitative or quantitative deficiencies of the platelet membrane glycoprotein ␣ IIb ␤ 3 . This is the first report of a molecular genetic basis for type I GT in dogs. As previously reported, a thrombasthenic Great Pyrenees dog (dog No. 1) experienced uncontrolled epistaxis despite results of coagulation screening tests, platelet quantitation, and von Willebrand factor quantitation that were within reference ranges. Platelet aggregation was minimal in response to agonists. Flow cytometry, autoradiography, and immunoblot experiments demonstrated either marked reduction or absence of glycoproteins ␣ IIb and ␤ 3 . In this study, we report the presence of a 14-base insertion in exon 13 and defective splicing of intron 13 in the ␣ IIb gene of two thrombasthenic dogs (Nos. 1 and 8). The insertion disrupted the fourth ␣ IIb calcium-binding domain, caused a shift in the reading frame and resulted in a premature termination codon. Possible consequences of this mutation include decreased ␣ IIb mRNA stability and production of truncated ␣ IIb protein that lacks the transmembrane and cytoplasmic domains and a large portion of the extracellular domain. We identified the dam, sire, and three littermates of dog No. 8 as carriers of the ␣ IIb mutation. Canine ␣ IIb and ␤ 3 genes share significant homology with the genes in human beings, making canine GT an excellent translational model for human GT. A defined molecular basis for canine GT will enhance ongoing gene therapy research and increase the understanding of structure-function relationships of this integrin.

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The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel.

Abstract: Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by a decrease or absence of functional platelet glycoprotein (GP) fib-Ma

Cited by 164 publications

References 34 publications

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Presentation and pattern of symptoms in 382 patients with Glanzmann thrombasthenia in Iran

Two Genetic Defects in α_IIb Are Associated with Type I Glanzmann's Thrombasthenia in a Great Pyrenees Dog: A 14-base Insertion in Exon 13 and a Splicing Defect of Intron 13

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The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel.

Abstract: Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by a decrease or absence of functional platelet glycoprotein (GP) fib-Ma

Cited by 164 publications

References 34 publications

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Presentation and pattern of symptoms in 382 patients with Glanzmann thrombasthenia in Iran

Two Genetic Defects in αIIb Are Associated with Type I Glanzmann's Thrombasthenia in a Great Pyrenees Dog: A 14-base Insertion in Exon 13 and a Splicing Defect of Intron 13

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Two Genetic Defects in α_IIb Are Associated with Type I Glanzmann's Thrombasthenia in a Great Pyrenees Dog: A 14-base Insertion in Exon 13 and a Splicing Defect of Intron 13