αIIbβ3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on<i>ITGA2B</i>and<i>ITGB3</i>mRNA splicing, expression, and structure-function

Jallu, Vincent; Dusséaux, Mathilde; Panzer, Simon; Torchet, M. F.; Hézard, Nathalie; Goudemand, Jenny; Brevern, Alexandre G. de; Kaplan, C.

doi:10.1002/humu.21179

Cited by 33 publications

(52 citation statements)

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“…GT is caused by nonsyndromic genetic variants across both ITGA2B (30 exons) and ITGB3 (15 exons) [D'Andrea et al., ; Peretz et al., ; Kannan et al., ; Jallu et al., ; Nurden et al., , ]. Approximately 200 mutations are currently found on the GT database (http://sinaicentral.mssm.edu/intranet/research/glanzmann/menu).…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…Whole genome sequencing will be required for a full analysis of the very large number of genetic variants known to be present on both genes (ITGA2B, 2315; ITGB3, 11652; http:www.ensembl/index.html.org, last accessed 7 April 2016). Remarkably, this same combination was located in homozygous form in a French patient reported by Jallu et al (2009) and both SNPs were again homozygous in GT50 of our study (Nurden et al, 2015). Sanger sequencing does not allow the assignment of a heterozygous polymorphism to its specific allele.…”

Section: Discussionmentioning

confidence: 54%

Linkage disequilibrium amongst ITGA2B and ITGB3 gene variants in patients with Glanzmann thrombasthenia confirms that most disease‐causing mutations are recent

Pillois

Nurden

2016

Br J Haematol

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We recently reported mutation analysis of the largest cohort of Glanzmann thrombasthenia (GT) patients so far examined. Sanger sequencing of coding regions, splice sites, upstream and downstream regions of the ITGA2B and ITGB3 genes identified 78 causal genetic variants (55 novel); 4 large deletions or duplications were also detected. We have now analysed the expression of non-causal gene polymorphisms in the sequenced regions of both genes in selected members of this cohort. We identified 10 mostly silent variants in ITGA2B and 37 in ITGB3; all were present in control donor databases. Three non-synonymous single nucleotide polymorphisms present were human platelet alloantigen (HPA) variants. A series of haplogroups, often including HPA-3b in ITGA2B, repeated with little variation across unrelated families of wide geographical origins and with different GT-causing mutations whether in ITGA2B or ITGB3. In contrast, a deleterious heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B shared a common ITGA2B haplogroup composed of at least five gene polymorphisms and re-occurred in seven European families with no known family relationships. Our results highlight the value of gene polymorphism analysis in GT and are consistent with the bulk of disease-causing mutations in GT being of recent origin.

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“…Electrostatic maps projected on van der Vaals molecular surfaces are valuable tools for studying the impact of mutations [33]. Figure S1 in supplementary material shows electrostatic maps projected on the 3D models of the L33 and P33 allelic forms viewed from the β3 knee.…”

Section: Resultsmentioning

confidence: 99%

Modeling and Molecular Dynamics of HPA-1a and -1b Polymorphisms: Effects on the Structure of the β3 Subunit of the αIIbβ3 Integrin

Jallu¹,

Poulain

Fuchs

et al. 2012

PLoS ONE

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BackgroundThe HPA-1 alloimmune system carried by the platelet integrin αIIbβ3 is the primary cause of alloimmune thrombocytopenia in Caucasians and the HPA-1b allele might be a risk factor for thrombosis. HPA-1a and -1b alleles are defined by a leucine and a proline, respectively, at position 33 in the β3 subunit. Although the structure of αIIbβ3 is available, little is known about structural effects of the L33P substitution and its consequences on immune response and integrin functions.Methodology/Principal FindingsA complete 3D model of the L33-β3 extracellular domain was built and a P33 model was obtained by in silico mutagenesis. We then performed molecular dynamics simulations. Analyses focused on the PSI, I-EGF-1, and I-EGF-2 domains and confirmed higher exposure of residue 33 in the L33 β3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 β3 form. The L33P substitution does not alter the local structure (residues 33 to 35) of the PSI domain, but modifies the structural equilibrium of the three domains.ConclusionsThese results provide a better understanding of HPA-1 epitopes complexity and alloimmunization prevalence of HPA-1a. P33 gain of structure flexibility in the β3 knee may explain the increased adhesion capacity of HPA-1b platelets and the associated thrombotic risk. Our study provides important new insights into the relationship between HPA-1 variants and β3 structure that suggest possible effects on the alloimmune response and platelet function.

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αIIbβ3 integrin: new allelic variants in Glanzmann thrombasthenia, effects onITGA2BandITGB3mRNA splicing, expression, and structure-function

Cited by 33 publications

References 50 publications

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

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

Linkage disequilibrium amongst ITGA2B and ITGB3 gene variants in patients with Glanzmann thrombasthenia confirms that most disease‐causing mutations are recent

Modeling and Molecular Dynamics of HPA-1a and -1b Polymorphisms: Effects on the Structure of the β3 Subunit of the αIIbβ3 Integrin

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