scholarly journals Two Genetic Defects in αIIbAre 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 ◽  
Vol 37 (6) ◽  
pp. 581-588 ◽  
Author(s):  
D. L. Lipscomb ◽  
C. Bourne ◽  
M. K. Boudreaux
Keyword(s):  
Genetic Defects ◽  
Type I ◽  
Glanzmann’S Thrombasthenia ◽  
Splicing Defect ◽  
Glanzmann's Thrombasthenia ◽  
Base Insertion

Abnormal Processing of the Glycoprotein IIb Transcript due to a Nonsense Mutation in Exon 17 Associated with Glanzmann’s Thrombasthenia

1995 ◽  
Vol 73 (05) ◽  
pp. 756-762 ◽  
Author(s):  
Yoshiaki Tomiyama ◽  
Hirokazu Kashiwagi ◽  
Satoru Kosugi ◽  
Masamichi Shiraga ◽  
Yoshio Kanayama ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Molecular Genetic ◽  
Genetic Defect ◽  
Nucleotide Sequence Analysis ◽  
Type I ◽  
Normal Amount ◽  
Immunoblot Assay ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
Pcr Products

SummaryWe analyzed the molecular genetic defect responsible for type I Glanzmann’s thrombasthenia in a Japanese patient. In an immunoblot assay using polyclonal anti-GPIIb-IIIa antibodies, some GPIIIa (15% of normal amount) could be detected in the patient’s platelets, whereas GPIIb could not (<2% of normal amount). Nucleotide sequence analysis of platelet GPIIb mRNA-derived polymerase chain reaction (PCR) products revealed that patient’s GPIIb cDNA had a 75-bp deletion in the 3’ boundary of exon 17 resulting in an in-frame deletion of 25 amino acids. DNA analysis and family study revealed that the patient was a compound heterozygote of two GPIIb gene defects. One allele derived from her father was not expressed in platelets, and the other allele derived from her mother had a 9644C → T mutation which was located at the position -3 of the splice donor junction of exon 17 and resulted in a termination codon (TGA). Moreover, quantitative analysis demonstrated that the amount of the abnormal GPIIb transcript in the patient’s platelets was markedly reduced. Thus, the C → T mutation resulting in the abnormal splicing of GPIIb transcript and the reduction in its amount is responsible for Glanzmann’s thrombasthenia.

Detection of Carriers in Glanzmann's Thrombasthenia

1983 ◽  
Vol 49 (03) ◽  
pp. 182-186
Author(s):  
G T E Zonneveld ◽  
E F van Leeuwen ◽  
A Sturk ◽  
J W ten Cate
Keyword(s):  
Bleeding Time ◽  
Periodic Acid ◽  
Type I ◽  
Clot Retraction ◽  
Periodic Acid Schiff ◽  
Glanzmann’S Thrombasthenia ◽  
Aggregation Response ◽  
Glanzmann's Thrombasthenia ◽  
Sds Page ◽  
Reduced State

SummaryQuantitative glycoprotein (GP) analysis of whole platelets or platelet membranes was performed by SDS-polyacrylamide gelelectrophoresis (SDS-PAGE) and periodic acid Schiff staining in the families of two unrelated Glanzmann’s thrombasthenia (GT) patients. Each family consisted of two symptom free parents, a symptom free daughter and a GT daughter. All symptom free members had a normal bleeding time, clot retraction and platelet aggregation response to adenosine 5’-diphosphate (ADP), collagen and adrenalin. Platelet Zw* antigen was normally expressed in these subjects. GT patiens, classified as a type I and II subject, showed reduced amounts of GP lib and of GP nia. Analysis of isolated membranes in the non-reduced state, however, showed that the amount of GP Ilia was also reduced in three of the four parents, whereas one parent (of the GT type I patient) and the two unaffected daughters had normal amounts of GP Ilia. Quantitative SDS-PAGE may therefore provide a method for the detection of asymptomatic carriers in GT type I and II.

scholarly journals Homozygous Cys542Arg substitution in GPIIIa in a Swiss patient with type I Glanzmann's thrombasthenia

1999 ◽  
Vol 105 (2) ◽  
pp. 523-531 ◽  
Author(s):  
Jian Ruan ◽  
Markus Schmugge ◽  
Kenneth J. Clemetson ◽  
Eric Cazes ◽  
Robert Combrie ◽  
...  
Keyword(s):  
Type I ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia

scholarly journals A Three Amino Acid Deletion in Glycoprotein IIIa Is Responsible for Type I Glanzmann's Thrombasthenia: Importance of Residues Ile325Pro326Gly327 for β3 Integrin Subunit Association

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 669-677 ◽  
Author(s):  
Marie-Christine Morel-Kopp ◽  
Cécile Kaplan ◽  
Valérie Proulle ◽  
Vincent Jallu ◽  
Chantal Melchior ◽  
...  
Keyword(s):  
Amino Acid ◽  
Restriction Site ◽  
Restriction Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Type I ◽  
Integrin Subunit ◽  
Wild Type ◽  
Amino Acid Deletion ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia

Abstract Glanzmann's thrombasthenia (GT) is a recessive autosomal bleeding disorder characterized by abnormal platelet aggregation due to a qualitative or quantitative defect of the glycoprotein (GP) IIb-IIIa complex (integrin αIIbβ3). We describe a new mutation in the GPIIIa gene responsible for type I GT in a consanguineous Algerian family. A discordance between phenotyping and genotyping of the GPIIIa-related HPA-1 platelet alloantigen system in three family members heterozygous for the disease suggested a genetic defect in the GPIIIa gene and a normal GPIIb gene. Sequence analysis of amplified genomic DNA fragments showed a 6-bp deletion in exon 7 of the GPIIIa gene resulting in the amino acid deletion/substitution (Ile325Pro326Gly327 → Met) and creating a new BspHI restriction site. Expression of the mutated integrin β3 subunit cDNA in Chinese hamster ovary cells showed that the cDNA gene was transcribed into a full-length β3 protein with an apparent molecular weight identical to wild-type β3 and accumulated as a single-chain molecule in the cell cytoplasm. The absence of heterodimeric complex formation of the mutant β3 protein with endogeneous αv was shown by immunoprecipitation experiments, intracellular immunofluorescent labeling, and a semiquantitative enzyme-linked immunosorbent assay using the αvβ3 complex-specific monoclonal antibodies LM609 and 23C6. Substitution of the methionine residue by a proline, present at position 326 of wild-type β3, did not restore the ability of the recombinant mutant β3 protein to associate with αv, suggesting that the Ile-Pro-Gly motif is located in a β3 domain important for integrin subunit interaction. The association of a BspHI restriction site with this newly identified mutation has allowed allele-specific restriction analysis of Algerian GT individuals and the identification of two new unrelated type I patients exhibiting the same mutation, suggesting that the described mutation might be significant in this population and that BspHI restriction analysis will provide a useful screening assay for antenatal diagnosis and genetic counselling.

Indication for allogeneic stem cell transplantation in Glanzmann’s thrombasthenia

2013 ◽  
Vol 33 (04) ◽  
pp. 305-312 ◽  
Author(s):  
K. Sauer ◽  
B. Winkler ◽  
M. Eyrich ◽  
P. G. Schlegel ◽  
V. Wiegering
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autosomal Recessive Disorder ◽  
Marrow Transplant ◽  
Haematopoietic Stem Cell ◽  
Current Status ◽  
Type I ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia

SummaryGlanzmann’s thrombasthenia (GT) is an autosomal recessive disorder characterized by a lack of thrombocyte aggregation due to the absence of thrombocyte glycoproteins IIb and αIIbβ3. The role of haematopoietic stem cell transplantation (HSCT) in GT remains controversial. However, HSCT offers the only curative approach for patients with a severe clinical phenotype.In this review, we will discuss the limitation of current status evidence and the specific risk of GT, in particular the alloimmunization and refractoriness to thrombocyte infusions. 19 successful HSCT in 18 GT type I patients have been reported. Mean age at transplantation was 5 years. All patients are still alive. The majority received sibling bone marrow transplant with busulfan and cyclophosphamid conditioning. GvHD incidence was within the normal range, but 10 patients showed alloimmunization of thrombocytes. Median follow up is 25 months.

scholarly journals Monocytes and platelets share the glycoproteins IIb and IIIa that are absent from both cells in Glanzmann's thrombasthenia type I

1983 ◽  
Vol 214 (2) ◽  
pp. 331-337 ◽  
Author(s):  
G Gogstad ◽  
Ø Hetland ◽  
N O Solum ◽  
H Prydz
Keyword(s):  
Platelet Membrane ◽  
Type I ◽  
Membrane Glycoproteins ◽  
Edta Treatment ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia

By means of an antiserum specific to the complex of the platelet membrane glycoproteins IIb and IIIa we demonstrate here that monocytes and purified monocyte membranes share these glycoproteins with platelets. The monocyte glycoprotein IIb-IIIa complex showed complete immunological identity with the platelet counterpart and, furthermore, dissociated after EDTA treatment exactly as did the platelet complex. In Glanzmann's thrombasthenia type I, monocytes as well as platelets lack this antigen completely.

Diagnosis of Heterozygotes in Glanzmann’s Thrombasthenia

1982 ◽  
Vol 48 (02) ◽  
pp. 217-221 ◽  
Author(s):  
H Stormorken ◽  
G O Gogstad ◽  
N O Solum ◽  
H Pande
Keyword(s):  
High Reliability ◽  
Type I ◽  
Bleeding Tendency ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
Immunochemical Methods

SummaryA study of a family with a propositus suffering from classical thrombasthenia type I has shown that the new immunochemical methods detect heterozygotes with high reliability. There was no overlapping between heterozygotes and normals, and the concentration of the glycoprotein IIb-IIIa-complex is remarkably constant around 50–60% in the heterozygotes. Furthermore, heterozygotes as a group show an increased bleeding tendency.

THE ARG-GLY-ASP(SER) SEQUENCE OF FIBRONECTIN, AND THE GLYCOPROTEIN IIB-IIIA COMPLEX ARE NOT INVOLVED IN FIBRONECTIN DEPENDENT PLATELET ADHESION IN FLOW

1987 ◽  
Author(s):  
P F E M Nievelstein ◽  
M Ottenhof-Rovers ◽  
M D Pierschbacher ◽  
J J Sixma
Keyword(s):  
Platelet Adhesion ◽  
Cell Attachment ◽  
Blood Platelets ◽  
Attachment Site ◽  
Type I ◽  
Shear Rates ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
Static Conditions ◽  
Induced Aggregation

Activated blood platelets interact with fibronectin through it to the glycoprotein IIb-IIIa(GPIIb-IIIa)-complex. The cell attachment site of fibronectin with its crucial arg-gly-asp-(-ser) (RGD(S))sequence is involved in this binding. We have studied the importance of this interaction for the fibronectin dependence of platelet adhesion under flow conditions. An RGDS-containing hexapeptide (GRGDSP) was compared with a non-reactive control peptide (GRGESP). The GRGDSP-peptide inhibited thrombin induced aggregation and adhesion under static conditions at 0.1 mM. This concentration had no effect on platelet adhesion to nonfibrillar collagen type I in flow. GRGDSP at 1 mM had a significant inhibitory effect at 1500 s™1 (8.8 ± 1.4 111In platelets* 105 /cm2, versus 19.8 ± 0.5 for the control). At lower shear rates of 800 and 300 s™1 , where platelet adhesion is also fibronectin dependent, no significant differences were obtained (respectively 11.7 ± 1.1 versus 15.2 ± 2.1, and 11.4 ± 1.0 versus 13.1 ± 0.7).The relation between GPIIb-IIIa and fibronectin dependence was investigated with platelets of a patient with Glanzmann’s thrombasthenia and monoclonal antibodies to GPIIb-IIIa, using endothelial cell matrix (ECM) as a surface. Platelets of normal controls or a patient with Glanzmann’s thrombasthenia showed a inhibition of adhesion in fibronectin free plasma, after the ECM had been preincubated with anti-fibronectin F(ab’)2, of respectively _J5 and 30 percent at 300 s™1 , and 43 and 65 percent at 1300 s™1 . Incubation of platelets with anti GPIIb-IIIa showed inhibition of platelet adhesion at high shear rates. Dependence on fibronectin for platelet adhesion was still observed, even though separate experiments had shown that these anti GPIIb-IIIa antibodies could block binding of radiolabeled fibronectin to thrombin activated platelets. These data suggest the existence of a second binding system from the RGD/GPIIb-IIIa system separate for the interaction of platelets with fibronectin, which may only function when fibronectin is present on a surface.

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