Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation

TLDR

Rac2, a Rho family GTPase that dominates neutrophil Rac activity, regulates actin dynamics and superoxide production, with the highly conserved Asp57 residue essential for GTP binding. A 5‑week‑old infant with recurrent bacterial infections was found to have neutrophils lacking Rac2 protein and carrying a Rac2 D57N mutation that binds GDP but not GTP, thereby inhibiting NADPH oxidase activation and superoxide production, establishing an inhibitory Rac2 mutation as a cause of human neutrophil immunodeficiency.

Abstract

A 5-week-old male infant presented with severe bacterial infections and poor wound healing, suggesting a neutrophil defect. Neutrophils from this patient exhibited decreased chemotaxis, polarization, azurophilic granule secretion, and superoxide anion (O 2 − ) production but had normal expression and up-regulation of CD11b. Rac2, which constitutes >96% of the Rac in neutrophils, is a member of the Rho family of GTPases that regulates the actin cytoskeleton and O 2 − production. Western blot analysis of lysates from patient neutrophils demonstrated decreased levels of Rac2 protein. Addition of recombinant Rac to extracts of the patient neutrophils reconstituted O 2 − production in an in vitro assay system. Molecular analysis identified a point mutation in one allele of the Rac2 gene resulting in the substitution of Asp57 by an Asn (Rac2 D57N ). Asp57 is invariant in all defined GTP-binding proteins. Rac2 D57N binds GDP but not GTP and inhibits oxidase activation and O 2 − production in vitro . These data represent the description of an inhibitory mutation in a member of the Rho family of GTPases associated with a human immunodeficiency syndrome.