Molecular defects in ITGA2B and ITGB3 genes in patients with Glanzmann thrombasthenia

Abstract

Summary. Background: Glanzmann thrombasthenia (GT) is an autosomal recessive inherited platelet function defect that is characterized by reduction in, or absence of, platelet aggregation in response to multiple physiologic agonists. The defect is caused by mutations in the genes encoding ITGA2B or ITGB3. This results in qualitative or quantitative abnormalities of the platelet receptor, aIIb-b3. Objectives: The aim of this study was to identify the mutations in GT patients and to correlate these with patient phenotype. Subjects and methods: A total of 45 unrelated patients with GT were enrolled in the present study to identify the causative molecular defects, and also to correlate their phenotype with their genotype. Platelet aggregation, flow cytometry, Western blotting, and mutation screening by conformation sensitive gel electrophoresis (CSGE) followed by sequencing were performed in all patients. Novel mutations were analyzed for penetrance in individual families. Results: A total of 22 novel mutations were identified in 45 unrelated GT patients. Mutations were identified in 36 of the 45 (80%) patients. Missense mutations were seen in most of the GT patients (59%). The remaining mutations were heterogeneous and were distributed throughout the length of the gene. Analysis of family members showed heterozygous mutations in all families. Conclusions: The severe type I GT was the most common subtype found in this study. Missense mutations were identified as the defects responsible for most GT patients. Carrier detection and genetic counseling in these families is a potentially effective alternative for decreasing the burden of severe type of GT.

Are bone defects in rare patients with Glanzmann's thrombasthenia associated withITGB3orITGA2Bmutations?

“…As for our patient, platelet Fg was severely decreased. Both Arg327His and Gly381Arg substitutions have been detected during epidemiological screening for GT in India while a heterozygous Gly381Arg substitution was mentioned in a preliminary report on a GT patient from Egypt [19,20]. Overall, then there is abundant evidence that the GT-like syndrome in our patient is due to the combined presence of the heterozygous Arg327His and Gly381Arg mutations.…”

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

“…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).…”

The international prospective Glanzmann Thrombasthenia Registry: treatment modalities and outcomes in non-surgical bleeding episodes in Glanzmann thrombasthenia patients

“…[6][7][8] GT patients commonly present in childhood with mucocutaneous bleeds (easy bruising, purpura, epistaxis, gingival bleeds or menorrhagia), 2,9 and often experience bleeds after dental extraction, surgery, delivery and trauma. Although the severity of bleeding may vary, GT is considered a severe bleeding disease as at least 75% of patients require blood and/or platelet transfusions at least once in their life.…”