PB1299 - Novel homozygous frameshift mutation of ITGB3 in a Chinese Glanzmann thrombasthenia patient with congenital skeletal defects

Background: Glanzmann thrombasthenia (GT) is an autosomal inherited bleeding disorder caused by dysfunction of integrin αIIbβ3. αIIb (CD41) and β3(CD61) are encoded by ITGA2B and ITGB3, respectively. Besides platelets, β3 is highly expressed in osteoclasts and plays an important role in bone metabolism. Whether GT patients with β3 deficiency are also suffer from bone pathology is unclear, limited 2 cases were reported.

Aims: To dissecting the molecular pathogenesis of GT patient with skeletal defects.

Methods: The 22-year-old female proband who presented with bleeding diathesis, multiple congenital bone defects and deformity in her right hand, and seven family members were included in the study. Complete blood count, blood smear, platelet aggregation test, thromboelastography and coagulation test were performed. The expression of CD41 and CD61 was measured by platelet immunofluorescence test-flow cytometry. The mutation was identified by the whole-exome sequencing and confirmed by Sanger sequencing. Mutation pathogenicity was evaluated using Protein Variation Severity Score 1 and Polymorphism Metrics 2. Three-dimensional structure modeling analysis of β3, X-ray of the right hand and bone denistometry of proband were performed.

Results: With the absence platelet aggregation, reduced αIIbβ3 expression and traceable inheritance pattern, GT in the proband was diagonsed. A novel homozygous frameshift mutation c.2143_2158 delins CT (p. Lys 715 Leu fs*36) of ITGB3 in the proband was confirmed (Figure 1). Modelling strongly suggested the mutation creates a truncation in cytoplasmic domains of β3 and results in the mutant β3/αIIbβ3 inactivated (Figure 2). The right forearm of proband showed osteopenia and no other gene mutations related to bone pathology were identified. The mutation likely contributes to bone pathophysiology.

Conclusion(s): A novel mutation of ITGB3 was identified in a GT patient with congenital skeletal defects. Our work expands ITGB3 mutation spectrum and enriched our understanding of GT. The relationship between GT and bone pathophysiology requires further investigation.