Wiskott-Aldrich syndrome (WAS) is caused by mutation in the WASP gene encoding the Wiskott-Aldrich syndrome protein. WASP's primary function is:

• A RAG1/RAG2 recombinase activity enabling V(D)J recombination for TCR and BCR diversity
• B Nucleation of actin polymerization via activation of the Arp2/3 complex, enabling immune synapse formation and platelet cytoskeletal organization ✓
• C IL-2 receptor gamma chain signaling for T and NK cell development
• D BTK (Bruton tyrosine kinase) activity for BCR signal transduction in B-cell maturation

Explanation

WASP (Wiskott-Aldrich Syndrome Protein) is a scaffolding protein expressed exclusively in hematopoietic cells that links signaling pathways to actin cytoskeletal reorganization. It binds CDC42 (GTPase) and activates the Arp2/3 complex, which nucleates branched actin polymerization. This is essential for immune synapse formation between T-cells and antigen-presenting cells, for TCR signaling amplification, for NK cell cytotoxicity, and for platelet shape change and function (explaining the thrombocytopenia with small platelets). The classic triad of WAS is thrombocytopenia, eczema, and immunodeficiency (combined T and B cell defect). RAG1/2 defects cause Omenn syndrome/SCID; IL-2Rγ mutations cause X-SCID; BTK mutations cause X-linked agammaglobulinemia.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.