A novel frameshift mutation in the ITGB3 gene leading to Glanzmann's thrombasthenia in a Saudi Arabian family

SummarySevere Glanzmann's thrombasthenia is relatively frequent in Iraqi-Jews and Arabs residing in Israel. We have recently described the mutations responsible for the disease in Iraqi-Jews – an 11 base pair deletion in exon 12 of the glycoprotein IIIa gene, and in Arabs – a 13 base pair deletion at the AG acceptor splice site of exon 4 on the glycoprotein IIb gene. In this communication we show that the Iraqi-Jewish mutation can be identified directly by polymerase chain reaction and gel electrophoresis. With specially designed oligonucleotide primers encompassing the mutation site, an 80 base pair segment amplified in healthy controls was clearly distinguished from the 69 base pair segment produced in patients. Patients from 11 unrelated Iraqi-Jewish families had the same mutation. The Arab mutation was identified by first amplifying a DNA segment consisting of 312 base pairs in controls and of 299 base pairs in patients, and then digestion by a restriction enzyme Stu-1, which recognizes a site that is absent in the mutant gene. In controls the 312 bp segment was digested into 235 and 77 bp fragments, while in patients there was no change in the size of the amplified 299 bp segment. The mutation was found in patients from 3 out of 5 unrelated Arab families. Both Iraqi-Jewish and Arab mutations were detectable in DNA extracted from blood and urine samples. The described simple methods of identifying the mutations should be useful for detection of the numerous potential carriers among the affected kindreds and for prenatal diagnosis using DNA extracted from chorionic villi samples.

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Glycoprotein lb Polymorphism in a Patient with Glanzmann’s Thrombasthenia Type I (Case Report)

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647280 ◽

1990 ◽

Vol 64 (01) ◽

pp. 181-181

Author(s):

J C Giltay ◽

W B J Gerrits ◽

J A van Mourik

Keyword(s):

Case Report ◽

Type I ◽

Glanzmann’S Thrombasthenia ◽

Glanzmann's Thrombasthenia

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Stimulated Glanzmann’s Thrombasthenia Platelets Produce Microvesicles

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649978 ◽

1995 ◽

Vol 74 (06) ◽

pp. 1533-1540 ◽

Cited By ~ 23

Author(s):

Pål André Holme ◽

Nils Olav Solum ◽

Frank Brosstad ◽

Nils Egberg ◽

Tomas L Lindahl

Keyword(s):

Complement System ◽

Shape Change ◽

Annexin V ◽

Platelet Surface ◽

Glanzmann’S Thrombasthenia ◽

Large Numbers ◽

Glanzmann's Thrombasthenia ◽

Series Of Experiments ◽

The Complement System ◽

Number Of Particles

SummaryThe mechanism of formation of platelet-derived microvesicles remains controversial.The aim of the present work was to study the formation of microvesicles in view of a possible involvement of the GPIIb-IIIa complex, and of exposure of negatively charged phospholipids as procoagulant material on the platelet surface. This was studied in blood from three Glanzmann’s thrombasthenia patients lacking GPIIb-IIIa and healthy blood donors. MAb FN52 against CD9 which activates the complement system and produces microvesicles due to a membrane permeabilization, ADP (9.37 μM), and the thrombin receptor agonist peptide SFLLRN (100 μM) that activates platelets via G-proteins were used as inducers. In a series of experiments platelets were also preincubated with PGE1 (20 μM). The number of liberated microvesicles, as per cent of the total number of particles (including platelets), was measured using flow cytometry with FITC conjugated antibodies against GPIIIa or GPIb. Activation of GPIIb-IIIa was detected as binding of PAC-1, and exposure of aminophospholipids as binding of annexin V. With normal donors, activation of the complement system induced a reversible PAC-1 binding during shape change. A massive binding of annexin V was seen during shape change as an irreversible process, as well as formation of large numbers of microvesicles (60.6 ±2.7%) which continued after reversal of the PAC-1 binding. Preincubation with PGE1 did not prevent binding of annexin V, nor formation of microvesicles (49.5 ± 2.7%), but abolished shape change and PAC-1 binding after complement activation. Thrombasthenic platelets behaved like normal platelets after activation of complement except for lack of PAC-1 binding (also with regard to the effect of PGE1 and microvesicle formation). Stimulation of normal platelets with 100 μM SFLLRN gave 16.3 ± 1.2% microvesicles, and strong PAC-1 and annexin V binding. After preincubation with PGE1 neither PAC-1 nor annexin V binding, nor any significant amount of microvesicles could be detected. SFLLRN activation of the thrombasthenic platelets produced a small but significant number of microvesicles (6.4 ± 0.8%). Incubation of thrombasthenic platelets with SFLLRN after preincubation with PGE1, gave results identical to those of normal platelets. ADP activation of normal platelets gave PAC-1 binding, but no significant annexin V labelling, nor production of microvesicles. Thus, different inducers of the shedding of microvesicles seem to act by different mechanisms. For all inducers there was a strong correlation between the exposure of procoagulant surface and formation of microvesicles, suggesting that the mechanism of microvesicle formation is linked to the exposure of aminophospholipids. The results also show that the GPIIb-IIIa complex is not required for formation of microvesicles after activation of the complement system, but seems to be of importance, but not absolutely required, after stimulation with SFLLRN.

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653864 ◽

1995 ◽

Vol 73 (05) ◽

pp. 756-762 ◽

Cited By ~ 25

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.

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Diversity of Glycoprotein Deficiencies in Glanzmann’s Thrombasthenia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1660085 ◽

1985 ◽

Vol 54 (03) ◽

pp. 626-629 ◽

Cited By ~ 4

Author(s):

M Meyer ◽

F H Herrmann

Keyword(s):

High Resolution ◽

Gel Electrophoresis ◽

Type Ii ◽

Two Dimensional ◽

Two Dimensional Gel Electrophoresis ◽

Structural Variant ◽

Glanzmann’S Thrombasthenia ◽

Crossed Immunoelectrophoresis ◽

Glanzmann's Thrombasthenia ◽

Platelet Proteins

SummaryThe platelet proteins of 9 thrombasthenic patients from 7 families were analysed by high resolution two-dimensional gel electrophoresis (HR-2DE) and crossed immunoelectrophoresis (CIE). In 7 patients both glycoproteins (GPs) IIb and Ilia were absent or reduced to roughly the same extent. In two related patients only a trace of GP Ilb-IIIa complex was detected in CIE, but HR-2DE revealed a glycopeptide in the position of GP Ilia in an amount comparable to type II thrombasthenia. This GP Ilia-like component was neither recognized normally by anti-GP Ilb-IIIa antibodies nor labeled by surface iodination. In unreduced-reduced two-dimensional gel electrophoresis two components were observed in the region of GP Ilia. The assumption of a structural variant of GP Ilia in the two related patients is discussed.

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Detection of Carriers in Glanzmann's Thrombasthenia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657357 ◽

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.

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A Glanzmann’s Thrombasthenia Cluster Among Iraqi Jews in Israel

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661184 ◽

1984 ◽

Vol 52 (03) ◽

pp. 230-231 ◽

Cited By ~ 35

Author(s):

U Seligsohn ◽

S Rososhansky

Keyword(s):

Total Population ◽

Carrier State ◽

Calculated Frequency ◽

Jewish Origin ◽

Glanzmann’S Thrombasthenia ◽

Glanzmann's Thrombasthenia

SummaryA country-wide survey of Glanzmann’s thrombasthenia in Israel identified 44 patients. The patients belong to 23 unrelated families, 17 of whom are of Iraqi Jewish origin. The frequency of thrombasthenia among Iraqi Jews in Israel (total population 270,000) is 1:7714 and thus the calculated frequency of the carrier state is 2.3%.

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A Case Report on Glanzmann’s Thrombasthenia: A Rare Platelet Function Disorder

Haematology Journal of Bangladesh ◽

10.37545/haematoljbd201818 ◽

2018 ◽

Vol 2 (02) ◽

pp. 59-60

Author(s):

Farida Yasmin ◽

Md. Anwarul Karim ◽

Chowdhury Yakub Jamal ◽

Mamtaz Begum ◽

Ferdousi Begum

Keyword(s):

Case Report ◽

Platelet Function ◽

The Body ◽

Presenting Symptoms ◽

Glanzmann’S Thrombasthenia ◽

Glanzmann's Thrombasthenia ◽

Platelet Function Disorders ◽

Recurrent Epistaxis ◽

Severe Epistaxis ◽

History Of

Epistaxis in children is one of the important presenting symptoms for attending emergency department in paediatric patients. Recurrent epistaxis is common in children. Although epistaxis in children usually occurred due to different benign conditions, it may be one of the important presenting symptoms of some inherited bleeding disorder. Whereas most bleeding disorders can be diagnosed through different standard hematologic assessments, diagnosing rare platelet function disorders may be challenging. In this article we describe one case report of platelet function disorders on Glanzmann’s thrombasthenia (GT). Our patient was a 10-year old girl who presented to us with history of recurrent severe epistaxis. She had a bruise on her abdomen and many scattered petechiae in different parts of the body. Her previous investigations revealed no demonstrable haemostatic anomalies. After performing platelet aggregation test, she was diagnosed as GT.

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