The Experts below are selected from a list of 701301 Experts worldwide ranked by ideXlab platform
Maha Othman - One of the best experts on this subject based on the ideXlab platform.
-
gene of the issue GP1BA gene mutations associated with bleeding
2017Co-Authors: Maha Othman, Jonas EmsleyAbstract:The GP1BA gene codes for the platelet GPIbα subunit of the glycoprotein GPIb-IX complex, which comprises four transmembrane polypeptides in total with GPIbα disulfide linked to GPIbβ and GPIX and G...
-
a novel d235y mutation in the GP1BA gene enhances platelet interaction with von willebrand factor in an iranian family with platelet type von willebrand disease
2012Co-Authors: Said Enayat, Jonas Emsley, Shirin Ravanbod, Maryam Rassoulzadegan, Mohammad Jazebi, Shirin Tarighat, F Ala, Maha OthmanAbstract:Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder with an intrinsic defect in platelets rather than von Willebrand factor (VWF), but has clinical and laboratory features similar to the more common type 2B VWD. The intriguing nature of the pathophysiology and molecular genetics of PT-VWD has created lengthy debate in literature regarding its discrimination from type 2B VWD, and essentially confirming DNA analysis as the gold standard in diagnosis and revealing pathologic mutations. In this report we identify a novel Asp235Tyrmutation in the GP1BA gene of two Iranian patients showing the PT-VWD phenotype who were originally misdiagnosed as type 2B VWD. By structural modelling of the mutant by introducing Tyr235 into the available crystal structure of the glycoprotein (GP)Ibα N-terminal domain, we observed the mutant Tyr235 generates a hydrophobic tip to the extended β-switch loop of GPIbα. Further modelling of the resulting complex with VWFA1 indicates this could result in an enhanced interface compared to wild-type Asp235. This data provides an update to the present knowledge about this rare disorder, and confirms the necessity of genetic testing for accurate diagnosis, and the importance of studying natural mutations to better understand molecular aspects of GPIbα-VWFA1 interaction.
-
platelet type von willebrand disease a rare often misdiagnosed and underdiagnosed bleeding disorder
2011Co-Authors: Maha OthmanAbstract:Platelet-type von Willebrand disease (PT-VWD) is an autosomal dominant rare bleeding disorder characterized by hyperresponsive platelets. This inherent platelet function defect is due to a gain-of-function mutation within the GP1BA gene coding for the platelet surface glycoprotein Ib alpha protein, the receptor for the adhesive protein von Willebrand factor (VWF). The defect results in excessive and unnecessary platelet-VWF interaction with subsequent removal of the hemostatically efficient high molecular weight VWF as well as platelets from the circulation, leading to thrombocytopenia and bleeding diathesis. Patients with PT-VWD present with mild to moderate mucocutaneous bleeding, which becomes more pronounced during pregnancy and following aspirin ingestion or drugs that have antiplatelet activity. Laboratory testing shows low VWF:ristocetin cofactor and low or normal VWF:antigen and characteristically an enhanced ristocetin-induced platelet agglutination (RIPA). These laboratory features are also indicators of the closely similar and more common bleeding disorder type 2B VWD. Simplified RIPA mixing assays, cryoprecipitate challenge, and flow cytometry can differentiate between the two disorders. However, the gold standard is to identify mutations within the VWF gene (indicating type 2B VWD) or the platelet GP1BA gene (confirming PT-VWD). Treatment is based on making a correct diagnosis of PT-VWD where platelet concentrates instead of VWF/factor VIII preparations should be administered. A recent fairly large retrospective/prospective registry-based international study showed that PT-VWD is very rare, likely to be misdiagnosed as type 2B VWD or idiopathic thrombocytopenic purpura, and represents 15% of type 2B VWD diagnoses.
François Lanza - One of the best experts on this subject based on the ideXlab platform.
-
a novel platelet type von willebrand disease mutation GP1BA p met255ile associated with type 2b malmo new york von willebrand disease
2016Co-Authors: Cecile Lavenubombled, Corinne Guitton, Arnaud Dupuis, Mariejeanne Baas, Celine Desconclois, Marie Dreyfus, Claudine Caron, Christian Gachet, Edith Fressinaud, François LanzaAbstract:Interaction between von Willebrand factor (VWF) and platelet GPIbα is required for primary haemostasis. Lack or loss-of-function in the ligand-receptor pair results in bleeding complications. Paradoxically, gain-of-function mutations in VWF or GPIbα also result in bleeding complications as observed in type 2B von Willebrand disease (VWD) and platelet-type- (PT-) VWD, respectively. A similar phenotype is observed with increased ristocetin-induced platelet agglutination and disappearance of the highest molecular weight multimers of VWF. We evaluated a patient with a bleeding disorder and a biological presentation compatible with type 2B VWD. VWF and platelet functional assays, sequencing of the VWF and GP1BA genes, and expression studies in HEK cells were performed. Sequencing of the VWF gene in the propositus revealed a heterozygous p.Pro1266Leu mutation previously found in type 2B VWD Malmo/New York. These variants are characterised by a mild phenotype and a normal VWF multimer composition suggesting the presence of a second mutation in our propositus. Sequencing of the GP1BA gene revealed a heterozygous c.765G>A substitution changing Met at position 255 of GPIbα to Ile. This new mutation is located in the β-switch domain where five other gain-of-function mutations have been reported in PT-VWD. Expression of GPIbα Ile255 in HEK GPIb-IX cells resulted in enhanced VWF binding compared to wild-type, similar to known PT-VWD mutations (p.Val249, p.Ser249 and p.Val255) indicating that it contributes to the propositus defects. This first report associating PT- with type 2B VWD illustrates the importance of combining biological assays with genetic testing to better understand the clinical phenotype.
-
deletion of human gp1bb and sept5 is associated with bernard soulier syndrome platelet secretion defect polymicrogyria and developmental delay
2011Co-Authors: Ingrid Bartsch, François Lanza, Kirstin Sandrock, Paquita Nurden, I Hainmann, Anna Pavlova, Andreas Greinacher, Uta Tacke, Michael Barth, Anja BusseAbstract:The bleeding disorder Bernard-Soulier syndrome (BSS) is caused by mutations in the genes coding for the platelet glycoprotein GPIb/IX receptor. The septin SEPT5 is important for active membrane movement such as vesicle trafficking and exocytosis in non-dividing cells (i.e. platelets, neurons). We report on a four-year-old boy with a homozygous deletion comprising not only glycoprotein Ibβ (GP1BB) but also the SEPT5 gene, located 5’ to GP1BB. He presented with BSS, cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect. The homozygous deletion of GP1BB and SEPT5, which had been identified by PCR analyses, was confirmed by Southern analyses and denaturing HPLC (DHPLC). The parents were heterozygous for this deletion. Absence of GPIbβ and SEPT5 proteins in the patient’s platelets was illustrated using transmission electron microscopy. Besides decreased GPIb/IX expression, flow cytometry analyses revealed impaired platelet granule secretion. Because the bleeding disorder was extremely severe, the boy received bone marrow transplantation (BMT) from a HLA-identical unrelated donor. After successful engraftment of BMT, he had no more bleeding episodes. Interestingly, also his mental development improved strikingly after BMT. This report describes for the first time a patient with SEPT5 deficiency presenting with cortical dysplasia (polymicrogyria), developmental delay, and platelet secretion defect.
-
Bernard-Soulier syndrome (Hemorrhagiparous thrombocytic dystrophy).
2006Co-Authors: François LanzaAbstract:Bernard-Soulier syndrome (BSS), also known as Hemorrhagiparous thrombocytic dystrophy, is a hereditary bleeding disorder affecting the megakaryocyte/platelet lineage and characterized by bleeding tendency, giant blood platelets and low platelet counts. This syndrome is extremely rare as only ~100 cases have been reported in the literature. Clinical manifestations usually include purpura, epistaxis, menorrhagia, gingival and gastrointestinal bleeding. The syndrome is transmitted as an autosomal recessive trait. The underlying defect is a deficiency or dysfunction of the glycoprotein GPIb-V-IX complex, a platelet-restricted multisubunit receptor required for normal primary hemostasis. The GPIb-V-IX complex binds von Willebrand factor, allowing platelet adhesion and platelet plug formation at sites of vascular injury. Genes coding for the four subunits of the receptor, GPIBA, GPIBB, GP5 and GP9, map to chromosomes 17p12, 22q11.2, 3q29, and 3q21, respectively. Defects have been identified in GPIBA, GPIBB, and GP9 but not in GP5. Diagnosis is based on a prolonged skin bleeding time, the presence of a small number of very large platelets (macrothrombocytopenia), defective ristocetin-induced platelet agglutination and low or absent expression of the GPIb-V-IX complex. Prothrombin consumption is markedly reduced. The prognosis is usually good with adequate supportive care but severe bleeding episodes can occur with menses, trauma and surgical procedures. Treatment of bleeding or prophylaxis during surgical procedures usually requires platelet transfusion.
-
Orphanet Journal of Rare Diseases BioMed Central Review
2006Co-Authors: Bernard-soulier Syndrome Thrombocytic, François LanzaAbstract:which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Bernard-Soulier syndrome (BSS), also known as Hemorrhagiparous thrombocytic dystrophy, is a hereditary bleeding disorder affecting the megakaryocyte/platelet lineage and characterized by bleeding tendency, giant blood platelets and low platelet counts. This syndrome is extremely rare as only ~100 cases have been reported in the literature. Clinical manifestations usually include purpura, epistaxis, menorrhagia, gingival and gastrointestinal bleeding. The syndrome is transmitted as an autosomal recessive trait. The underlying defect is a deficiency or dysfunction of the glycoprotein GPIb-V-IX complex, a platelet-restricted multisubunit receptor required for normal primary hemostasis. The GPIb-V-IX complex binds von Willebrand factor, allowing platelet adhesion and platelet plug formation at sites of vascular injury. Genes coding for the four subunits of the receptor, GPIBA, GPIBB, GP5 and GP9, map to chromosomes 17p12, 22q11.2, 3q29, and 3q21, respectively. Defects have been identified in GPIBA, GPIBB, and GP9 but not in GP5. Diagnosis is based on a prolonged skin bleeding time, the presence of a small number of very large platelets (macrothrombocytopenia), defective ristocetin-induced platelet agglutination and low or absen
Maria A Lazzari - One of the best experts on this subject based on the ideXlab platform.
-
identificacion por nuestro grupo de una nueva mutacion en el gen GP1BA p w246l asociada al fenotipo pt vwd sexta mutacion reportada internacionalmente
2014Co-Authors: Adriana I Woods, Analia Sanchezluceros, Emilse Bermejo, Juvenal Paiva, Maria Fabiana Alberto, Silvia H Grosso, Ana Catalina Kempfer, Maria A LazzariAbstract:Fil: Woods, Adriana Ines. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
-
identification of p w246l as a novel mutation in the GP1BA gene responsible for platelet type von willebrand disease
2014Co-Authors: Adriana I Woods, Analia Sanchezluceros, Emilse Bermejo, Juvenal Paiva, Maria Fabiana Alberto, S H Grosso, Ana C Kempfer, Maria A LazzariAbstract:Platelet-type von Willebrand disease (PT-VWD) and type 2B von Willebrand disease (2B-VWD) are rare bleeding disorders characterized by increased ristocetin-induced platelet aggregation (RIPA) at low concentrations of ristocetin. Diagnosis of either condition is not easy and the differential diagnosis between the two entities is especially challenging as evidenced by high levels of misdiagnosis of both conditions, but particularly PT-VWD. Five mutations in the GP1BA gene related to PT-VWD and less than 50 patients are currently reported worldwide. We herein describe a patient with severe bleeding symptoms, macrothrombocytopenia, mild spontaneous platelet aggregation, positive RIPA at 0.3 and 0.4 mg/mL, von Willebrand factor ristocetin cofactor (VWF:RCo) to antigen (VWF:Ag) / VWF:Ag ratio, and RIPA mixing tests and cryoprecipitate challenge positive for PT-VWD. GP1BA gene was studied in the patient, in his mother, and in 100 healthy control subjects. We identified a heterozygous substitution G > T located at nucleotide 3805 in the g.DNA of the patient's GP1BA gene, resulting in a Trp to Leu amino acid change at residue 246 (p.W246L). This mutation was absent in his unaffected mother and also in the 100 controls, and was predicted as damaging by in silico analysis. The residue W246 is located within the VWF-binding region and exists in a strongly conserved position in the phylogenetic tree, which is expected to be unable to tolerate substitutions without changing its functional characteristics. These findings argue strongly in favor of the view that this substitution does not represent a polymorphism and is therefore responsible for the PT-VWD phenotype of the patient.
F Hill - One of the best experts on this subject based on the ideXlab platform.
-
distinguishing between type 2b and pseudo von willebrand disease and its clinical importance
2006Co-Authors: Mohammad S Enayat, Andrea M Guilliatt, William Lester, Jonathan T Wilde, M.d. Williams, F HillAbstract:SummaryPseudo-von Willebrand disease (p-VWD) and type 2B von Willebranddisease (VWD) have similar phenotypic parameters and clinical symptoms,but different aetiologies. Fourteen individuals from five families with ahistorical diagnosis of type 2B VWD but with no mutation in the vonWillebrand factor gene were re-investigated for the possibility of p-VWD,using platelet aggregation in the presence of cryoprecipitate. p-VWD wasconfirmed by targeted DNA sequencing of the glycoprotein Iba gene,identifying a heterozygous Glycine 233 Valine substitution. This studysuggests that p-VWD may be under diagnosed, and that platelet aggregationin the presence of cryoprecipitate is useful in differentiating this disorderfrom type 2B VWD.Keywords: pseudo-von Willebrand disease, type 2B von Willebrand disease,platelet aggregation with cryoprecipitate, mutation, GPIba gene. short report a 2006 The Authorsdoi:10.1111/j.1365-2141.2006.06078.x Journal Compilation a 2006 Blackwell Publishing Ltd, British Journal of Haematology, 133, 664–666
Etsuro Ito - One of the best experts on this subject based on the ideXlab platform.
-
physical association of the patient specific gata1 mutants with runx1 in acute megakaryoblastic leukemia accompanying down syndrome
2006Co-Authors: Issay Kitabayashi, Rika Kanezaki, Tsutomu Toki, Seiji Watanabe, Yoshihiro Takahashi, Kiminori Terui, Etsuro Ito, Tsutomu Toki, Yoshihiro TakahashiAbstract:Mutations of the GATA1 gene on chromosome X have been found in almost all cases of transient myeloproliferative disorder and acute megakaryoblastic leukemia (AMKL) accompanying Down syndrome (DS). Although most GATA1 mutations lead to the expression of GATA1s lacking the N-terminal activation domain, we recently found two novel GATA1 proteins with defects in another N-terminal region. It has been suggested that loss of the N-terminal portion of GATA1 might interfere with physiological interactions with the critical megakaryocytic transcription factor RUNX1, and this would imply that GATA1s is not able to interact properly with RUNX1. However, the interaction domain of GATA1 remains controversial. In this study, we show that GATA1 binds to RUNX1 through its zinc-finger domains, and that the C-finger is indispensable for synergy with RUNX1. All of the patient-specific GATA1 mutants interacted efficiently with RUNX1 and retained their ability to act synergistically with RUNX1 on the megakaryocytic GP1bα promoter, whereas the levels of transcriptional activities were diverse among the mutants. Thus, our data indicate that physical interaction and synergy between GATA1 and RUNX1 are retained in DS-AMKL, although it is still possible that increased RUNX1 activity plays a role in the development of leukemia in DS.
