A nonsense mutation in the GPIIb heavy chain (Ser 870 → stop) impairs platelet GPIIb–IIIa expression

Vinciguerra, Christine; Khélif, Abderrahim; Alemany, Mònica; Morlé, François; C, Grenier; Uzan, G; Gulino, D.; Dechavanne, M; Négrier, Claude

doi:10.1046/j.1365-2141.1996.d01-1903.x

Cited by 26 publications

(13 citation statements)

References 33 publications

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“…12 and in exons 1 and 3 of the GPIIIa gene responsible for GT 17,18 were easily detected by DGGE analysis (data not shown). Moreover, mutations introduced in the promoter region of the GPIIb (a gift from Dr G. Uzan, Inserm U217, Grenoble, France) presented an altered melting behaviour with heteroduplex analysis (data not shown).…”

Section: Choice Of Experimental Conditionsmentioning

confidence: 86%

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Description of 10 new mutations in platelet glycoprotein IIb (αIIb) and glycoprotein IIIa (β3) genes

et al. 2001

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In this study we have used denaturing gradient gel electrophoresis (DGGE) for identifying sequence alterations in glycoprotein (GP) IIb and IIIa genes from 20 patients affected by Glanzmann's thrombasthenia. These patients were from 16 different families. Using computer modelling, we divided the promoters, coding sequences and flanking splicing regions, in 31 segments for the GPIIb gene and 19 domains for the GPIIIa gene. We were able to find a mutation potentially affecting GPIIb-IIIa expression or function in 16 patients out of 20. In six patients from three families, the gypsy mutation modifying the splice donor site of intron 15 of the GPIIb gene was detected. In the other patients, 10 novel mutations were characterised, which were located either in the GPIIb gene (nine cases) or in the GPIIIa gene (one case). The type of mutation was nonsense mutation (one case), missense mutation (five cases), small insertion of 1 bp (one case) and splicing modifications (three cases). Among these genetic events, three were directly responsible for Glanzmann's thrombasthenia, four were localised in regions known to be involved in GPIIb-IIIa complex expression and three mutations were potentially responsible for Glanzmann's thrombasthenia.

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Section: Choice Of Experimental Conditionsmentioning

confidence: 86%

“…Glanzmann's thrombasthenia diagnosis was evoked on clinical presentation and platelet aggregation analysis. Western blot and flow cytometry analyses were performed as previously described 12 to study platelet GPIIb-IIIa expression. Consanguinity was known in five families and in relatives of two index cases.…”

Section: Patientsmentioning

confidence: 99%

Description of 10 new mutations in platelet glycoprotein IIb (αIIb) and glycoprotein IIIa (β3) genes

et al. 2001

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“…2674delA is near the proteolytic cleavage site. Ser870Stop around the same region allows heterodimer formation, impairs maturation [14]. Six missense mutations with four in the -propeller region, one in the calf-2 region and two in the GPIIb heavy chain region forming subunit interface in the IIb 3 heterodimer were detected.…”

Section: Discussionmentioning

confidence: 97%

Novel mutations in GP IIb gene in Glanzmann's thrombasthenia from India

Vijapurkar

Ghosh²,

Shetty

2009

Platelets

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The integrin GPIIb-IIIa plays an important role in platelet activation and plug formation. Quantitative and qualitative dysfunction in this receptor causes Glanzmann's thrombasthenia (GT) and leads to a bleeding tendency. Mutations in the GPIIb or GPIIIa gene are known to be responsible for the inherited form of this disease, which is characterized by mucocutaneous bleeding and other clinically severe bleeding manifestations. GT is an autosomal inherited platelet function. Mutations in the GPIIIa gene but not GPIIb gene in GT patients from Western India have been studied. Hence, this study was designed and included for the first time two mutation detection strategies: single strand conformation polymorphism and conformation sensitive gel electrophoresis followed by sequencing. Patients diagnosed as GT in our laboratory were screened for mutations. We report 12 mutations in 13 patients, of which 11 are novel mutations. Six mutations were missense, four were deletions and two were splice junction mutations. The study thus identifies novel mutations in the GPIIb gene in patients from Western India, implicating the importance of certain amino acids in structure-function correlations as well as enabling prenatal diagnosis in these families.

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“…Homozygous or compound heterozygous nonsense mutations all gave type I GT, findings compatible with a block in αIIbβ3 biogenesis and a high probability of nonsense‐mediated mRNA decay [Vinciguerra et al., ; Arias‐Salgado et al., ; Peretz et al., ; Jallu et al., ]. A specific example is the homozygous ITGA2B exon 19 c.1882C>T transition common to two Swiss siblings (GT39a/b) with type I GT.…”

Section: Discussionmentioning

confidence: 99%

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of theITGA2BandITGB3Genes in a Large International Cohort

et al. 2015

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We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in seven unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits, thereby interfering with integrin maturation and/or function. Our study extends knowledge of GT and the pathophysiology of an integrin.

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A nonsense mutation in the GPIIb heavy chain (Ser 870 → stop) impairs platelet GPIIb–IIIa expression

Cited by 26 publications

References 33 publications

Description of 10 new mutations in platelet glycoprotein IIb (αIIb) and glycoprotein IIIa (β3) genes

Description of 10 new mutations in platelet glycoprotein IIb (αIIb) and glycoprotein IIIa (β3) genes

Novel mutations in GP IIb gene in Glanzmann's thrombasthenia from India

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of theITGA2BandITGB3Genes in a Large International Cohort

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