Novel mutations in RASGRP2, which encodes CalDAG-GEFI, abrogate Rap1 activation, causing platelet dysfunction.

Area of Science:

• Hematology
• Genetics
• Molecular Biology

Background:

• Platelet dysfunction, including Glanzmann's thrombasthenia, can arise from genetic defects affecting αIIbβ3 integrin function.
• The RASGRP2 gene encodes CalDAG-GEFI, a protein crucial for the inside-out activation of αIIbβ3 integrins in platelets and neutrophils.

Observation:

• Two unrelated families presented with bleeding diathesis and platelet dysfunction.
• Next-generation sequencing and whole-exome sequencing identified novel, function-disrupting homozygous RASGRP2 mutations in affected individuals.
• CalDAG-GEFI expression was significantly reduced in patient platelets, with impaired nucleotide exchange activity observed for the p.Ser381Phe variant.

Findings:

• Homozygous RASGRP2 mutations led to CalDAG-GEFI deficiency, causing agonist-specific defects in platelet αIIbβ3 integrin activation and aggregation.
• Neutrophil integrin activation was also impaired in patients.
• Granule secretion, platelet spreading, and clot retraction remained largely unaffected.

Implications:

• These findings represent the first reported cases of CalDAG-GEFI deficiency due to homozygous RASGRP2 mutations.
• This deficiency impacts both leukocyte and platelet integrin activation, highlighting a critical role for CalDAG-GEFI in immune and hemostatic functions.
• Identifies novel genetic targets for understanding and potentially treating bleeding disorders and immune deficiencies.