Academic literature on the topic 'GP1BA'
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Journal articles on the topic "GP1BA"
1
Peck, Rachel C., Sarah Westbury, Lucy Fitzgibbon, Neil V. Morgan, Jose Rivera, Walter H. Kahr, Nihr BioResource, et al. "Comprehensive Description of Monoallelic GP1BA Variants Associated with Thrombocytopenia." Blood 136, Supplement 1 (November 5, 2020): 34–35. http://dx.doi.org/10.1182/blood-2020-133987.
Full textAbstract:
GP1BA encodes the glycoprotein (GP) 1bα subunit of the GP1b/IX/V complex, the platelet receptor for von Willebrand factor (VWF) and a mediator of outside-in signalling that contributes to platelet activation. Biallelic variants in GPIBA that prevent surface expression of GPIB/IX/V cause the recessive disorder Bernard Soulier Syndrome (BSS; OMIM #23100) in which there is often severe bleeding caused by thrombocytopenia and platelet dysfunction. Thrombocytopenia has also been associated with monoallelic missense variants in the GP1bα R loop (residues 227-242) which enhance VWF binding (platelet-type von Willebrand disease (pVWD); OMIM #177820). Other monoallelic GPIBA missense variants such as the Bolzano variant (p.Ala172Val; OMIM #153670) have been associated with dominant thrombocytopenia without altered VWF levels. In order to better describe the relationship between monoallelic GPIBA variants and thrombocytopenia we evaluated data from the NIHR BioResource for Rare Diseases, (NBR-RD) and the Inherited Platelet Disorders programmes at the Universities of Birmingham (UK), Murcia (Spain) and Toronto (Canada) in which patients with unexplained platelet disorders underwent diagnostic next generation sequencing. Using the BeviMed method for genetic association we compared the genotypes at rare nonsynoymous variants of 105 unrelated thrombocytopenia cases (platelet count (PLT) <130x109/L or the human phenotype ontology term 'HP 001873 thrombocytopenia') in the NBR-BR with those of 10,152 unrelated participants without thrombocytopenia. There was a strong statistical association (posterior probability 0.97) between dominantly inherited GPIBA variants and thrombocytopenia. Considering the five variants within the NBR-BR that drove this association alongside genotype data from the other case collections, we identified a total of 21 different monoallelic GPIBA coding variants that were rare (gnomAD allele frequency <1/1000) and had a CADD pathogenicity score >15. These were present in 29 index cases (18 females, median age 37 years) with unexplained thrombocytopenia and included the variant predicting the p.Asn150Ser substitution which was identified in seven independent index cases. The variants comprised 18 missense, two inframe insertions (one with an additional missense change) and one insertion resulting in a frame shift. Seven had been previously associated with thrombocytopenia. Sixteen of the variants predicted amino acid substitutions or single residue insertions within the GP1bα leucine rich repeat region (LRR; residues 48-200) or in adjacent regions of the LRR N- and C-terminal caps. Cases with variants in the LRR region typically displayed mild mucocutaneous bleeding, abnormal bleeding after minor trauma or surgery and heavy menstrual bleeding. The platelet count was typically 60-100 x109/L and mean platelet volume greater than 11 fL. There were two missense variants in the GP1bα R loop that have been previously associated with pVWD and two further previously unreported missense variants in the cytoplasmic domain. The final variant was a monoallelic single nucleotide insertion predicted to cause a frame shift and absent expression of GP1bα and has been previously reported as a biallelic variant associated with BSS. These data indicate that in a multicentre cross-sectional cohort of cases with otherwise unexplained thrombocytopenia, monoallelic missense GPIBA variants affecting the LRR or adjacent regions were more prevalent than R loop variants associated with pVWD or variants causing absent GP1bα expression associated with biallelic BSS. The LRR region contains the GP1bα-VWF binding site which is predicted to be disrupted by the missense variants observed in this study. The LRR region is also the location of the GP1bα Bolzano variant and six other monoallelic variants previously associated with thrombocytopenia in previous single case reports. These observations extend the repertoire of GPIBA variants associated with thrombocytopenia and although requiring experimental confirmation of pathogenicity, suggest a common molecular pathogenesis for dominant GPIBA-associated thrombocytopenia in which reduced circulating platelet numbers arises from defective GP1bα-VWF interactions. Figure Disclosures Turro: Tachyon Ventures: Other: Partner & Scientific Director.
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de Siqueira, Lucia Helena, Miriam P. Beltrame, Fernanda P. G. Cunha, Marina P. Colella, Joyce M. Annichino-Bizzacchi, Erich V. de Paula, and Margareth C. Ozelo. "Six Novel Mutations Identified in the Glycoproteins Ib Alpha, Ib Beta and IX Genes Among Twenty-Two Unrelated Patients with Bernard-Soulier Syndrome in Brazil." Blood 118, no. 21 (November 18, 2011): 1156. http://dx.doi.org/10.1182/blood.v118.21.1156.1156.
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Abstract Abstract 1156 Introduction: Bernard-Soulier syndrome (BSS) is a rare hereditary bleeding disorder, caused by mutations within the glycoprotein (GP) Ib alpha, GP Ib beta and GP IX genes that encode three of four subunits of the platelet GP Ib-V-IX adhesion receptor. In the present study we evaluated the mutations involved in the diagnosis of BSS from twenty-two unrelated patients. Patients and Methods: All patients were followed in two large bleeding disorder reference centers in Brazil. The diagnosis of BSS was established based on the presence of mucocutaneous bleeding and macrotrombocytopenia, and was confirmed by platelet ristocetin aggregation and flow cytometry for the platelet GP Ib alpha (CD 42b), GP Ib beta (CD 42c), and GP IX (CD 42a). Available first- and second-degree relatives were also contacted for clinical, laboratory and molecular evaluation. Genomic DNA from all index cases was used for sequence analysis of the three genes, GP1BA, GP1BB and GP9, and the results were confirmed in relatives when available. Results: Twenty-two unrelated patients with the confirmed diagnosis of BSS were enrolled in this study. Among twenty-two index cases, twenty-one had one or two mutations identified, including six novel mutations. We also identified two mutations that have been previously reported, GP1BA C209S (Simsek, et al., 1994), and GP9 A140T (Wang, et al., 2004). The six novel mutations correspond to conserved regions, and they consist of two mutations in the GP1BA (L51R, and L99P), three in GP1BB (M-25A, L72R, and L112P), and one in GP9 (P52Q). One of these novel mutations, the GP1BB L112P was observed in twelve of twenty-two unrelated cases. PCR-restriction fragment length analysis of genomic DNA from a hundred normal unrelated controls were performed to evaluate the presence of GP1BA L99P and GP1BB L112P mutations by using the AlwN I and Alu I restriction enzymes, respectively. All controls were negative for both mutations. Interestingly, when we analyzed the relatives of the index cases indentified with the mutations GP1BA L99P and GP1BB M-25A, we found evidence of mild macrotrombocytopenia in the heterozygote carriers of these mutations. The relatives heterozygous for GP1BB L112P showed normal platelet count and morphology. However, in three index cases with mild macrotrombocytopenia, GP1BB L112P in heterozygosity was the only mutation identified. Furthermore, site-directed mutagenesis was carried out to evaluate the expression of the novel mutations GP1BA L51R, and GP1BA L99P. Compared to the GP1BA wild-type, both mutations were only minimally expressed in CHO bIX cells, which stably express GP Ib beta and GP IX. Conclusions: We identified in this study eight distinct mutations among twenty-two unrelated SBS patients, including six novel mutations. The GP1BB L112P mutation was found in twelve of the twenty-two index cases, suggesting that this could be due to a founder effect. Identifying such a frequent mutation in this population of BSS patients will be helpful for genetic diagnosis of this condition in Brazil. Furthermore these mutations significantly add to the mutation database of BSS and will inevitably provide insights into the function of GP Ib-V-IX. Disclosures: No relevant conflicts of interest to declare.
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Savoia, Anna, Shinji Kunishima, Patrizia Noris, Nuria Pujol-Moix, Dermot Kenny, Nurit Rosenberg, Margaret L. Rand, et al. "International Consortium for the Study of Clinical and Molecular Aspects of Bernard-Soulier Syndrome." Blood 118, no. 21 (November 18, 2011): 707. http://dx.doi.org/10.1182/blood.v118.21.707.707.
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Abstract Abstract 707FN2 Bernard-Soulier syndrome (BSS) is an extremely rare inherited bleeding disorder characterized by a defect of the GPIb/IX/V complex, which is essential for hemostasis, as the GPIbα subunit binds to subendothelial von Willebrand factor. Since the identification of the first mutation in 1990, almost one hundred cases carrying mutations in the GP1BA, GP1BB, and GP9 genes have been described. Most of the mutations prevent the coordinated association of the complex or binding to the von Willebrand factor. BSS is usually transmitted as a recessive trait with giant platelets and severe bleeding tendency. However, there are families with a dominant mild form, in which the affected individuals have only moderate macrothrombocytopenia and bleeding tendency. A correct definition of the clinical and laboratory features, together with accurate genotype/ phenotype correlation studies, remains essential for understanding the molecular basis of the disease and managing patients appropriately. Moreover, it is important to understand the variability of clinical manifestations. Since BSS is rare with an estimated prevalence of 1:1,000,000, an International Consortium has recently been established to collect a large series of cases and families worldwide. At present, the Consortium has been compiling data from 165 unrelated families, of which 50% have not been previously described. In this cohort, the molecular genetic testing reveals more than 30 novel mutations, confirming the wide spectrum of alterations responsible for the disease. Data from 65 unrelated families (69 patients) mainly from France, Italy and Japan show that 23 have mutations in GP9 and 29 in GP1BB. In the remaining 13 families, the defective gene is GP1BA. In agreement with the view that BSS is an extremely rare disease, 53 probands carried homozygous mutations, 10 are compound heterozygous, and 2 hemizygous because of a 22q11 deletion of the DiGeorge syndrome. The mean age of patients at diagnosis was 18 years (range 0–75 years) of which 27 were males and 38 females. Misdiagnosis of autoimmune thrombocytopenia was frequent and 26 patients were previously treated with steroids, intravenous immunoglobulins and/or splenectomy. Except two Japanese cases without any bleeding manifestations, patients presented with a variable bleeding diathesis measured by the World health Organization bleeding scale: grades 1, 2, 3 and 4 in 9, 18, 19 and 10 patients, respectively. The mean platelet count was 64×109/L (range 24–130) as determined by microscopy. In contrast, using a cell counter, thrombocytopenia was more severe (45×109/L; range 5–125). The mean platelet mean diameter was larger than in controls and varied from 2.9 to 7.5 mm. Ristocetin-induced platelet agglutination was absent or lower than 22% of normal response in all patients. Flow cytometry revealed a defective expression of the GPIb/IX/V expression in all patients. Correlating between expression data and gene affected, we found that the expression of GP1ba was often undetectable in patients with GP1BA mutations whereas it was higher, 8% and 17%, in patients with mutations of GP1BB and GP9, respectively. Instead, the GPIX mean level was 14%, 8% and 25% in patients with GP9, GP1BB and GP1BA mutations. The expression of GPV was higher than that of the other subunits, being more than 30% regardless of which gene was mutated. This is the largest cohort of BSS patients characterized to date. These patients together with the other 100 cases not yet included in the BSS database will enable correlations of the molecular genetic defects, receptor expression and clinical manifestations observed in BSS patients. Disclosures: Zieger: CSL Behring Hattersheim: Research Funding.
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Mekchay, Ponthip, Praewphan Ingrungruanglert, Kanya Suphapeetiporn, Darintr Sosothikul, Wilawan Ji-au, Supang Maneesri Le Grand, Nipan Israsena, and Ponlapat Rojnuckarin. "Study of Bernard–Soulier Syndrome Megakaryocytes and Platelets Using Patient-Derived Induced Pluripotent Stem Cells." Thrombosis and Haemostasis 119, no. 09 (July 28, 2019): 1461–70. http://dx.doi.org/10.1055/s-0039-1693409.
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AbstractBernard–Soulier syndrome (BSS) is a hereditary macrothrombocytopenia caused by defects in the glycoprotein (GP) Ib-IX-V complex. The mechanism of giant platelet formation remains undefined. Currently, megakaryocytes (MKs) can be generated from induced pluripotent stem cells (iPSCs) to study platelet production under pharmacological or genetic manipulations. Here, we generated iPSC lines from two BSS patients with mutations in different genes (GP1BA and GP1BB: termed BSS-A and BSS-B, respectively). The iPSC-derived MKs and platelets were examined under electron microscopy and stained by immunofluorescence to observe proplatelet formation and measure platelet diameters which were defined by circumferential tubulin. BSS-iPSCs produced abnormal proplatelets with thick shafts and tips. In addition, compared with the normal iPSCs, the diameters were larger in platelets derived from BSS-A and BSS-B with the means ± standard deviations of 4.34 ± 0.043 and 3.88 ± 0.045 µm, respectively (wild-type iPSCs 2.61 ± 0.025 µm, p < 0.001). Electron microscopy revealed giant platelets with the abnormal demarcation membrane system. Correction of BSS-A and BSS-B-iPSCs using lentiviral vectors containing respective GP1BA and GP1BB genes improved proplatelet structures and platelet ultrastructures as well as reduced platelets sizes. In conclusion, the iPSC model can be used to explore molecular mechanisms and potential therapy for BSS.
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Arter, Zhaohui Liao, Caitlin Yatogo, Michael C. Chicka, and Jeffrey L. Berenberg. "The Mystery of "Magic Blood" - Familial Macrothrombocytopenia Associated with a Novel Variant in GP1BA Gene." Blood 134, Supplement_1 (November 13, 2019): 2380. http://dx.doi.org/10.1182/blood-2019-122384.
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Introduction: Inherited macrothrombocytopenias comprise a heterogeneous group of rare inherited disorders characterized by decreased platelet count with enlarged platelet size. Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein that is encoded by GP1BA gene, and functions as a receptor for von Willebrand factor (VWF). Mutations in the GP1BA gene are seen in Bernard-Soulier syndrome (BSS). Here we describe a family with an isolated giant platelet disorder and a novel variant in the GP1BA gene following an autosomal dominant mode of inheritance. In our kindred this variant was not associated with clinical history or specific laboratory evidence of BSS. Case Presentation: 34-year-old female reported first being diagnosed with macrothrombocytopenia at the age of 13 on routine blood work. The patient and 11 of her relatives spanning 5 generations have reported asymptomatic macrothrombocytopenia (Figure 1), described as "Magic Blood" by her family. Her platelet count fell below 20,000/microL during one of her pregnancies. She was treated as idiopathic thrombocytopenic purpura (ITP) and was given corticosteroids to increase platelet count without improvement. On presentation, patient's complete blood count was significant for low platelet at 55,000/microL and macrothrombocytes were observed on blood smear. Methods/Results: VWF assays, including Factor VIII activity, VWF Ag, and Ristocetin Cofactor, were within normal limits. VWF multimer analysis revealed a normal pattern and distribution of bands. Patient had a normal platelet aggregation in response to ADP, Collagen, Epinephrine, Ristocetin and Arachidonate. Flow Cytometry detected normal GP Ib and GP IIb/ IIIa expression. Whole exome sequencing and copy number analysis of 29 genes associated with thrombocytopenia revealed a c.97T>G substitution in the GP1BA gene predicted to result in the amino acid substitution p.Cys33Gly (Figure 2). To our knowledge, this variant has not been reported in the literature or public databases. To confirm this novel variant is the cause of the familiar macrothrombocytopenia, two relatives with macrothrombocytopenia, a maternal uncle and a first cousin, also underwent genetic testing and were found to have the same variant. Discussion: Variants in GP1BA are associated with both autosomal dominant and recessive forms of BSS and with autosomal dominant platelet-type VWD. Our kindred is surprisingly asymptomatic given the location and specific amino acid substitution generated by the variant. Amino acid residue p.Cys33 resides in an extracellular N-terminal domain that is critical for VWF binding and proper assembly of the GP1B-IX complex. A heterozygous substitution involving the same amino acid residue defined as p.Cys33Arg was observed in two patients with macrothrombocytopenia with no reported bleeding complications (MC, unpublished data). Substitution of a nearby cysteine residue defined as p.Cys20Gly has been reported in a case of monoallelic chronic macrothrombocytopenia without bleeding diathesis similar to our patient. Amino acid residues p.Cys20 and p.Cyc33 are highly conserved among divergent species and substitution of these amino acid residues appears to not be tolerated. Substitution of other cysteine amino acid residues in the extracellular domain of the GP1BA protein (p.Cys81 and p.Cys225) has also been reported in patients with biallelic BSS, suggesting that perturbation of cysteine amino acid residues is likely to affect protein structure and function. Conclusion:We think the p.Cys33Gly substitution found in our patient and her relatives is likely to be a primary cause of monoallelic GP1BA-associated macrothrombocytopenia. It is important to distinguish inherited macrothrombocytopenia from ITP in order to avoid unnecessary and potentially toxic treatment. Disclosures No relevant conflicts of interest to declare.
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Nagy, Zoltan, Timo Vögtle, Mitchell J. Geer, Jun Mori, Silke Heising, Giada Di Nunzio, Ralph Gareus, et al. "The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions." Blood 133, no. 4 (January 24, 2019): 331–43. http://dx.doi.org/10.1182/blood-2018-09-877787.
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Abstract Conditional knockout (KO) mouse models are invaluable for elucidating the physiological roles of platelets. The Platelet factor 4-Cre recombinase (Pf4-Cre) transgenic mouse is the current model of choice for generating megakaryocyte/platelet-specific KO mice. Platelets and leukocytes work closely together in a wide range of disease settings, yet the specific contribution of platelets to these processes remains unclear. This is partially a result of the Pf4-Cre transgene being expressed in a variety of leukocyte populations. To overcome this issue, we developed a Gp1ba-Cre transgenic mouse strain in which Cre expression is driven by the endogenous Gp1ba locus. By crossing Gp1ba-Cre and Pf4-Cre mice to the mT/mG dual-fluorescence reporter mouse and performing a head-to-head comparison, we demonstrate more stringent megakaryocyte lineage-specific expression of the Gp1ba-Cre transgene. Broader tissue expression was observed with the Pf4-Cre transgene, leading to recombination in many hematopoietic lineages, including monocytes, macrophages, granulocytes, and dendritic and B and T cells. Direct comparison of phenotypes of Csk, Shp1, or CD148 conditional KO mice generated using either the Gp1ba-Cre or Pf4-Cre strains revealed similar platelet phenotypes. However, additional inflammatory and immunological anomalies were observed in Pf4-Cre-generated KO mice as a result of nonspecific deletion in other hematopoietic lineages. By excluding leukocyte contributions to phenotypes, the Gp1ba-Cre mouse will advance our understanding of the role of platelets in inflammation and other pathophysiological processes in which platelet-leukocyte interactions are involved.
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Bray, Paul F., Timothy D. Howard, Eric Vittinghoff, David C. Sane, and David M. Herrington. "Effect of genetic variations in platelet glycoproteins Ibα and VI on the risk for coronary heart disease events in postmenopausal women taking hormone therapy." Blood 109, no. 5 (November 14, 2006): 1862–69. http://dx.doi.org/10.1182/blood-2006-03-013151.
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Abstract Millions of women still use postmenopausal hormone therapy (HT). We genotyped 2090 women in Heart and Estrogen/progestin Replacement Study for functional polymorphisms in GP1BA and GP6 and assessed the coronary heart disease (CHD) event rate over 5.8 years of follow-up. In patients receiving placebo, there was an increased CHD death/myocardial infarction (MI)/unstable angina (UA) event rate in carriers of the GP1BA −5C allele (adjusted [adj] P = .006). HT increased the hazard ratio (HR) of CHD events in patients with the GP1BA −5TT genotype by 16% and reduced the HR in patients with the TC+CC genotypes by 46% (adj interaction P < .001). HT reduced the HR in patients with the GP6 13254TT genotype by 17% but increased the HR in patients with the TC+CC genotypes by 35% (adj interaction P < .001). Furthermore, HT increased the HR of CHD events in patients with the GP1BA −5TT plus GP6 13254TC+CC genotypes by 57% and reduced the HR in patients with the GP1BA −5TC+CC plus GP6 13254TT genotypes by 55% (adj interaction P < .001). In postmenopausal women with established CHD, these polymorphisms of platelet genes were predictors of CHD events and significantly modified the effects of HT on CHD risk. It will be important to replicate these findings in other studies.
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Skalníková, Magdalena, Kateřina Staňo Kozubík, Jakub Trizuljak, Zuzana Vrzalová, Lenka Radová, Kamila Réblová, Radka Holbová, et al. "A GP1BA Variant in a Czech Family with Monoallelic Bernard-Soulier Syndrome." International Journal of Molecular Sciences 23, no. 2 (January 14, 2022): 885. http://dx.doi.org/10.3390/ijms23020885.
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Bernard-Soulier syndrome (BSS) is a rare inherited disorder characterized by unusually large platelets, low platelet count, and prolonged bleeding time. BSS is usually inherited in an autosomal recessive (AR) mode of inheritance due to a deficiency of the GPIb-IX-V complex also known as the von Willebrand factor (VWF) receptor. We investigated a family with macrothrombocytopenia, a mild bleeding tendency, slightly lowered platelet aggregation tests, and suspected autosomal dominant (AD) inheritance. We have detected a heterozygous GP1BA likely pathogenic variant, causing monoallelic BSS. A germline GP1BA gene variant (NM_000173:c.98G > A:p.C33Y), segregating with the macrothrombocytopenia, was detected by whole-exome sequencing. In silico analysis of the protein structure of the novel GPIbα variant revealed a potential structural defect, which could impact proper protein folding and subsequent binding to VWF. Flow cytometry, immunoblot, and electron microscopy demonstrated further differences between p.C33Y GP1BA carriers and healthy controls. Here, we provide a detailed insight into its clinical presentation and phenotype. Moreover, the here described case first presents an mBSS patient with two previous ischemic strokes.
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Barozzi, Serena, Valeria Bozzi, Daniela De Rocco, Tania Giangregorio, Patrizia Noris, Anna Savoia, and Alessandro Pecci. "A Novel Mutation in GP1BB Reveals the Role of the Cytoplasmic Domain of GPIbβ in the Pathophysiology of Bernard-Soulier Syndrome and GPIb-IX Complex Assembly." International Journal of Molecular Sciences 22, no. 19 (September 22, 2021): 10190. http://dx.doi.org/10.3390/ijms221910190.
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Bernard-Soulier syndrome (BSS) is an autosomal-recessive bleeding disorder caused by biallelic variants in the GP1BA, GP1BB, and GP9 genes encoding the subunits GPIbα, GPIbβ, and GPIX of the GPIb-IX complex. Pathogenic variants usually affect the extracellular or transmembrane domains of the receptor subunits. We investigated a family with BSS caused by the homozygous c.528_550del (p.Arg177Serfs*124) variant in GP1BB, which is the first mutation ever identified that affects the cytoplasmic domain of GPIbβ. The loss of the intracytoplasmic tail of GPIbβ results in a mild form of BSS, characterized by only a moderate reduction of the GPIb-IX complex expression and mild or absent bleeding tendency. The variant induces a decrease of the total platelet expression of GPIbβ; however, all of the mutant subunit expressed in platelets is correctly assembled into the GPIb-IX complex in the plasma membrane, indicating that the cytoplasmic domain of GPIbβ is not involved in assembly and trafficking of the GPIb-IX receptor. Finally, the c.528_550del mutation exerts a dominant effect and causes mild macrothrombocytopenia in heterozygous individuals, as also demonstrated by the investigation of a second unrelated pedigree. The study of this novel GP1BB variant provides new information on pathophysiology of BSS and the assembly mechanisms of the GPIb-IX receptor.
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Gollomp, Kandace, and Mortimer Poncz. "Gp1ba-Cre or Pf4-Cre: pick your poison." Blood 133, no. 4 (January 24, 2019): 287–88. http://dx.doi.org/10.1182/blood-2018-11-887513.
Full textDissertations / Theses on the topic "GP1BA"
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De, Rocco Daniela, and Rocco Daniela De. "STUDIO CLINICO E MOLECOLARE DELLA SINDROME DI BERNARD-SOULIER." Doctoral thesis, Università degli studi di Trieste, 2015. http://hdl.handle.net/10077/10848.
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2013/20142013/2014
La sindrome di Bernard-Soulier (BSS) è una rara piastrinopenia ereditaria causata da alterazioni a livello del complesso glicoproteico GPIb-IX-V, presente sulla membrana piastrinica e responsabile della adesione delle piastrine in seguito a danno vascolare. La BSS si trasmette come malattia autosomica recessiva (BBSA1) e i pazienti affetti presentano piastrine giganti e severi episodi di sanguinamento. Tuttavia in tempi recenti sono state descritte delle famiglie con una forma dominante nota come BSSA2. In questi pazienti la piastrinopenia è moderata e le piastrine presentano un volume leggermente aumentato. Finora sono state individuate solo 5 varianti in eterozigosi nel BSSA2:, 4 nel gene GP1BA e 1 in GP1BB. Fatta eccezione per p.Ala172Val del gene GP1BA che è relativamente frequente nella la popolazione Italiana, le altre 4 sono state descritte in singole famiglie. I pochi casi di cui disponiamo, soprattutto per la forma recessiva non ci permettono di avere informazioni sui meccanismi patogenetici e sulla sua evoluzione nel tempo. Per questo motivo è stato istituito un Consorzio Internazionale per lo studio della BSS grazie al quale è stato possibile raccogliere i dati clinici e molecolari di 132 famiglie. Tutte le informazioni sono state inserite in un database (BSS Consortium database) attualmente gestito dal nostro laboratorio e consultabile dai gruppi di studio che hanno aderito al Consorzio. Inoltre per aumentare le informazioni sulle varianti identificate nel BSSA1 abbiamo incrementato i dati molecolari delle famiglie del Consorzio con i dati di altre 79 famiglie descritte in letteratura, raggiungendo un totale di 211 famiglie. Tutte le mutazioni identificate in queste famiglie sono state poi inserite in un database pubblico disponibile in rete (LOVD: Leiden Open Variation Database). La raccolta e l’elaborazione dei dati ci ha permesso di chiarire alcuni aspetti clinici e molecolari della malattia. Tuttavia data l’eterogeneità genetica e l’elevata espressione fenotipica gli studi genotipo-fenotipo si sono rivelati difficili da eseguire. Nonostante le molte informazioni acquisite, il database risulta ancora incompleto e limitato; per questo motivo è necessario raccogliere nuovi casi e inserire assieme alle varianti anche i relativi studi funzionali che si rivelano indispensabili per poter definire l’effetto delle varianti sul complesso GPIb-IX-V. Nell’ambito invece dello studio e caratterizzazione della forma meno grave di BSS (BSSA2) sono stati selezionati 120 pazienti piastrinopenici senza diagnosi caratterizzati da piastrine grandi. In questi pazienti sono stati analizzati i geni GP1BA, GP1BB e GP9 e sono state identificate 11 diverse varianti: 1 nonsense, 2 mutazioni di framshift, 1 mutazione nel codone di inizio e 5 varianti missense. Gli studi funzionali eseguiti sulle varianti missense per stabilire il loro ruolo patogenetico sono ancora in corso. Tuttavia se gli studi dovessero confermare la loro patogenicità 11 pazienti su 120 risulterebbero BSSA2 e questa forma dovrebbe essere considerata una tra le piastrinopenie ereditarie più frequenti in Italia. In conclusione grazie a questo studio è stato possibile raccogliere la più ampia casistica di pazienti affetti da BSSA1 fin’ora descritta e ottenere numerose informazioni sia sulla clinica che sulle mutazioni coinvolte. Il BSS Consortium database permetterà ai clinici che hanno partecipato allo studio di osservare nel tempo l’andamento della malattia nei pazienti e di ottenere informazioni utili per stabilire un corretto protocollo per la presa in carico dei pazienti. Infine la caratterizzazione di nuove forme di BSSA2 rappresenta il punto di partenza per descrivere al meglio la malattia BSSA2 sia dal punto di vista clinico che molecolare. In futuro sarà quindi indispensabile estendere il BSS Consortium database anche alla forma BSSA2.
XXVII Ciclo
XXVII Ciclo
1979
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Wenger, Roland Hugo. "Platelet molecular biology : cloning and characterisation of the platelet-specific genes CTAP-III and GPIba /." Bern, 1990. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Zarpellon, Alessandro. "Platelet interactions with a-thrombin and serotonin." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425112.
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The aim of the first part of this thesis was to study platelets from people with essential thrombocytosis. Platelets from ET patients present several abnormalities. We focused on the abnormalities related with serotonin, in particular we wanted :
1) to determine the sub-cellular distribution of the neurotransmitter
2) to evaluate 5-HT transport in platelets either untreated or pre-incubated with reserpine, a known inhibitor of serotonin transport inside the dense granules
3) to establish whether the decreased accumulation of serotonin in pathological platelets was due to a decreased number of dense granules
4) to investigate the efficiency of the dense granules to accumulate basic amines;
5) to determine the amounts of ATP and Ca2+ contained in the dense granules
6) to evaluate the role of tyrosine kinases in the tranport of serotonin in platelets of MPDs subjects.
7) to analyze the serotonin-induced platelet activation (cytosolic [Ca2+] increase).
The second part of this thesis performed at the Scripps Research Institute (La Jolla, CA) in the laboratory directed by prof. Z.M. Ruggeri was to precisely define the functional role of tyrosine sulfation in the a-thrombin binding to GpIba, a receptor present in platelets, that play a pivotal role in haemostasis and thrombosis.
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Coburn, Leslie Ann. "Studies of platelet gpib-alpha and von willebrand factor bond formation under flow." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/39565.
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Understanding the differential bonding mechanics underlying bleeding disorders is of crucial importance to human health. In this research insight is provided into how four of these bleeding disorders (each with somewhat similar clinical characteristics), work at the molecular bond level. The bleeding diseases studied here can result from defects in the platelet glycoprotein (GP) Ibα the von Willebrand factor (vWF) molecule, or the ADAMTS-13 enzyme. Types 2B and 2M von Willebrand Disease (VWD) result in excess bleeding, yet type 2B has increased binding affinity between platelet GPIbα and vWF, while type 2M has decreased binding affinity between these two molecules. Platelet type VWD (pt-VWD) causes mutations in the GPIbα molecule and has similar characteristics to type 2B VWD. Further, in thrombotic thrombocytopenic purpura, bleeding results when there is a lack of active ADAMTS-13 enzyme. Each disease results in patient bleeding, but due to different mechanisms. This dissertation will explore the bonding mechanics between GPIbα and vWF and how they are altered in each disease state. To observe the GPIbα-vWF bonding mechanics, rolling velocities, transient tethering lifetimes, and tether frequency were determined using a parallel plate flow chamber. Data from these experiments suggest that wt-wt interactions are force dependent and have biphasic catch-slip bonding behavior. The data show that the shear stress at which the maximum mean stop time occurs differs between gain-of-function and loss-of-function mutations. Using similar methods, we study the changes resulting from pt-VWD mutations in GPIbα, and find that the catch bond seen for wt-wt interactions is lost for these mutations. Further, the data suggest that interactions with gain-of-function GPIbα mutations may be transport rather than force dependent. Finally, how the GPIbα-vWF tether bond changes for thrombotic thrombocytopenic purpura was also investigated to show that the bond lifetime in the absence of the enzyme is increased presenting a possible rationale for why bleeding occurs in this disease. Overall, the data show how the bonding mechanics of the GPIbα-vWF tether bond differ in four bleeding diseases. Further, these observations offer potential explanations for how these changes in the bonding mechanism may play a role in the observed patient bleeding.
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Carvalhais, Virgínia Maria Dinis. "Variabilidade genética das glicoproteínas plaquetárias GPIba e GPIIIa e a sua possível associação com o risco trombótico em doentes com Diabetes mellitus tipo 2." Master's thesis, 2010. http://hdl.handle.net/1822/10861.
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Dissertação de mestrado em Genética MolecularAs patologias vasculares são a principal causa de mortalidade e morbilidade na Diabetes mellitus tipo 2. Uma vez que um endotélio vascular íntegro é fundamental para a homeostasia, eventos isquémicos são frequentes nos indivíduos com Diabetes mellitus tipo 2. Na isquemia arterial, a exposição do conteúdo da placa de ateroma leva à activação das plaquetas por intermédio das glicoproteínas existentes na superfície das mesmas. O objectivo principal deste estudo é verificar se a presença de polimorfismos nas glicoproteínas plaquetárias poderão estar associados com o aparecimento de isquemia arterial do membro inferior nos indivíduos com DM tipo 2. Para isso, estudou-se por PCRRFLP os SNPs HPA-2 e KOZAK na GPIbα, o PlA1/A2 na GPIIIa, e um VNTR na GPIbα. Verificou-se que existem diferenças estatisticamente significativas para o polimorfismo VNTR entre o grupo controlo e o grupo com DM tipo 2. O polimorfismo KOZAK parece estar associado ao aparecimento de isquemia arterial do membro inferior em indivíduos com DM tipo 2. Estes resultados sugerem que o polimorfismo KOZAK poderá contribuir para um aumento da probabilidade de desenvolver isquemia arterial do membro inferior em indivíduos com DM tipo 2. Os nossos resultados também evidenciam a importância do estudo dos polimorfismos plaquetários uma vez que podem contribuir para estabelecer um perfil genético de risco em indivíduos com DM tipo 2.
Vascular diseases are the most important cause of mortality and morbidity in patients with type 2 diabetes mellitus. Once a functional endothelium is important for homeostasis, ischaemic events are frequent in patients with type 2 diabetes mellitus. In arterial ischaemia, an exposition to contents of aterome plaque leads to platelet activation by glycoproteins that exist in platelets. The main goal of this study is to search if the presence of platelet glycoproteins polymorphisms are associated with arterial ischaemia of lower limbs in type 2 diabetes mellitus patients. It was analyze the HPA-2 and KOZAK SNPs in GPIbα, the PlA1/A2 SNP in GPIIIa and a VNTR in GPIbα, by PCR-RFLP. There were statistically significant differences for VNTR polymorphism between control group and type 2 diabetes mellitus group. It seems that the KOZAK polymorphism is associated with the presence of arterial ischaemia of lower limbs in type 2 diabetes mellitus patients. These results suggest that KOZAK polymorphism could contribute for an increased probability of developing arterial ischaemia of lower limbs in type 2 diabetes mellitus patients. Our results also show the importance of the study of polymorphisms in platelets since it could establish a genetic risk profile in patients with type 2 diabetes mellitus.
Centro de Investigação em Tecnologias da Saúde - Projecto (AL/12/2006/CESPU)
Book chapters on the topic "GP1BA"
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"Inhibitors of Platelet Adhesion: VWF-GP1b/IX and Collagen-GPVI Inhibitors." In New Therapeutic Agents in Thrombosis and Thrombolysis, 479–92. CRC Press, 2016. http://dx.doi.org/10.3109/9781420069242-31.
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Schaub, Robert G. "Inhibitors of Platelet Adhesion: VWF-GP1b/IX and Collagen-GPVI Inhibitors." In Fundamental and Clinical Cardiology Series, 457–70. Informa Healthcare, 2009. http://dx.doi.org/10.3109/9781420069242.026.
Full textConference papers on the topic "GP1BA"
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Silva, Gustavo Figueiredo da, Bruno Mattei Lopes, Vinicius Moser, and Leslie Ecker Ferreira. "Impact of pharmacogenetics on aspirin resistance: a systematic review." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.663.
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Background: Pharmacogenetics promises better control of diseases, such as Cardiovascular disease (CVD). Acetylsalicylic acid, aspirin, prevents the formation of an activating agent of platelet aggregation and vasoconstriction, and it is used to prevent CVD. Nevertheless, patients may have treatment failure, causing recurrence and increased mortality, due to medication adherence, drug- drug interactions, aspirin-independent thromboxane A2 synthesis or genetic variants. In this sense, genetic variants have been related with aspirin resistance (AR). Objective: To evaluate the evidence of impact of genetic variants on AR through systematic literature review. Design and setting: Systematic review. Methods: Articles published since 2009 in MEDLINE/PubMed, Cochrane, Scopus, LILACS and SCIELO were systematically screened. Results: The genetic variants rs1126643 (ITGA2), rs3842787 (PTGS1), rs20417 (PTGS2) and rs5918 (ITGB3) were the most studied. As for the relevance of the genetic variants studied, of the 64 evaluated, 14 had statistical significance (p <0.05, 95% CI) in at least one article. Among them, the following have had unanimous. Results: rs1371097 (P2RY1), rs1045642 (MDR1), rs1051931 and rs7756935 (PLA2G7), rs2071746 (HO1), rs1131882 and rs4523 (TBXA2R), rs434473 (ALOX12), rs9315042 (ALOX5AP) and rs662 (PON1). While these differ in real interference in AR: rs5918 (ITGB3), rs2243093 (GP1BA), rs1330344 (PTGS1) and rs20417 (PTGS2). Conclusion: As limitations of our study, we highlight the non-uniform methodologies of the analyzed articles, as well as population differences. It is also noteworthy that pharmacogenetics is an expanding area. Therefore, further studies are needed to better understand the association between genetic variants and AR, as well as the practical application.
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Malehmir, M., D. Pfister, S. Gallage, M. Szydlowska, D. Inverso, E. Kotsiliti, V. Leone, et al. "Platelet GPIba is a mediator and potential interventional target for NASH and subsequent liver cancer." In 35. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0038-1677172.
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Wyler, B., and K. J. Clemetson. "THE ROLE OF GPIb IN PLATELET ACTIVATION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642922.
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Platelet membrane glycoprotein lb (GPIb) is known to contain a receptor for von Willebrand factor (vWf) and for thrombin. The role of GPIb in platelet activation was investigated by comparing the effect of removal of the binding sites by specific proteolysis with that of blocking them using specific antibodies. Specific removal of the 45 kDa outer part of GPIb by treatment of platelets with human leukocyte elastase caused loss of platelet agglutination response to von Willebrand factor (vWf) but also a weaker activation by thrombin similar to that found with Bernard-Soulier syndrome platelets which lack GPIb. Removal of the major part of the external region of the GPIba chain, including the 45 kDa domain, by calcium activated protease or by chymotrypsin, produced similar effects. The 45 kDa region of GPIba was purified by tryptic cleavage of isolated glycocalicin followed by gel filtration. Antibodies to this fragment were produced in rabbits and showed high specificity and affinity for the 45 kDa polypeptide. Fab fragments of IgG prepared from this anti serum affect platelet response to vWf and thrombin in a dose-dependent way. In both protease-treated and antibody-treated platelets the reduced response to thrombin, but not to vWf could be overcome by increasing the dose of thrombin. In contrast to removal of the 45 kDa domain, antibody treatment affected not only the platelet response to vWf and thrombin but also to collagen, ADP, PAF and arachidonic acid. Only the response to the calcium ionophore A23,187 was unaltered.Though not the essential receptor GPIb is clearly involved in platelet response to thrombin. A possible mechanism could involve a conformational change in the cytoplasmic/inter-membranous part of GPIb induced by binding of thrombin to the 45 kDa domain. Binding of antibodies might affect platelet activation by other agonists via a general down regulation effect. These results support the two receptor models for thrombin activation of platelets as proposed for other cell -types. In platelets the first receptor appears to be GPIb but the second receptor has not yet been identified.
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Yamamoto, K., H. Kawasaki, K. Suzuki, K. Tanoue, G. Kosaki, and H. Yamazaki. "AMINO ACID SEQUENCE OF THE THROMBIN-BINDING SITE ON PLATELET GLYCOPROTEIN Ib." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642924.
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Amino acid sequence of the thrombin-binding site on platelet glycoprotein (GP) Ib was determined and the effects of the synthesized analogous peptides on thrombin-induced aggregation were studied. Crude platelet membrane fraction solubilized with 5mM dithiothreitol and 0.2% Tween 20 was applied to a WGA-Sepharose. The bound fractions were eluted with 0.3M N-actylglucosamine, then applied to a TM60 ( a monoclonal antibody against GP Ib)-Affi-gel column. Only one GP was bound to the column and was eluted with 50mM glycine-HCl, pH3.0, containing 0.2% Tween 20. SDS-PAGE showed a single band of 130kDa, corresponding to GP Ib alpha chain (GP Ibα). When the purified GP Ibα was digested with trypsin, two fragments (94kDa . and 43kDa) were obtained. The 43kDa fragment was shown to bind to both affinity colomns of TM60- and thrombin-Affi-gel, while the 94kDa fragment did not bind to either Affi-gel. When the same experiment was performed using chymotrypsin, three fragments (94kDa, 45kDa and 39kDa) were observed. On TM60- and thrombin-Affi-Gel columns, the smaller fragments (45kDa and 39kDa) were bound to both columns. However, on. thrombin-Affi-Gel column, 39kDa fragment was found in both unbound and bound fractions. It showed that the 45kDa fragment interacts with thrombin with a higher affinity than the 39kDa fragment. These results indicate that the thrombin-binding site is located on the "tail" portion of GPIba, especially on a chymotryptic cleavage site.Then 43kDa tryptic fragment was purified and its partial amino acid sequence was analyzed using gas phase amino acid sequence analyzer. Based on its amino acid sequence, several analogous oligopeptides were synthesized. Three peptides (#1-10, #11-23, #17-28) inhibited 0.05 U/ml thrombin-induced aggregations of washed human platelets in dose-dependent manners. IC50 were in the range of L50-550μM for each of these peptides.
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Lopez, J. A., D. W. Chung, K. Fujikawa, F. S. Hagen, T. Papavannopoulou, and G. J. Roth. "MOLECULAR CLONING OF HUMAN PLATELET GLYCOPROTEIN Ib." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642927.
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Glycoprotein Ib (GPIb) mediates von Willebrand factor-dependent platelet adhesion and participates in the resulting platelet activation process. In the present investigation, the primary structure of human platelet GPIb was studied. GPIb and its proteolytic fragment glycocalicin were purified to near homogeneity from human platelets by affinity chromatography using wheat germ agglutinin and anti-GPIb monoclonal antibody (D. Nugent, University of Washington) coupled to Sepharose. GPIba chain, β chain, and glycocalicin were isolated, reduced and carboxymethylated, and then fragmented by trypsin and S. aureus V8 protease. Peptides were isolated by HPLC and subjected to amino acid sequence analysis. Approximately 200 amino acid residues were identified. Affinity purified rabbit antibodies directed against the a chain, the ft chain, and glycocalicin were prepared and shown to be monospecific by Western blot analysis. Total RNA was prepared from human erythroleukemia cells grown in the presence of phorbol acetate. Poly(A)+ RNA was selected and used to prepare a cDNA library in λgt11. The library was screened with [125]I-labeled polyclonal antibody to glycocalicin. The clone with the largest cDNA insert was sequenced and shown to code for amino acid sequences corresponding to those determined by Edman degradation of glycocalicin. The predicted amino acid sequence contains at least six tandem repeats of 24 amino acids that are highly homologous with 13 repeats present in leucine rich α2 glycoprotein of human plasma. Another region in the protein contains a second repeat rich in threonine and serine, which shows some homology to a 9 amino acid repeat in the connecting region of human factor V. This region is probably the major site of attachment of clusters of O-linked carbohydrate in GPIbα. These results indicate that human platelet glycoprotein Ibα has a multi-domain structure composed of a number of repetitive sequences. Supported in part by grants from the American Heart Association, Robert Wood Johnson Foundation, Veterans Administration, and National Institutes of Health.
Reports on the topic "GP1BA"
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Russell, David W. Greater Philadelphia Bioinformatics Alliance (GPBA) 3rd Annual Retreat 2005. Fort Belvoir, VA: Defense Technical Information Center, November 2005. http://dx.doi.org/10.21236/ada439983.
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