Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation
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 (O2/-) production but had normal expression and up-regulation of CD11b. Rat2, which constitutes >96% of the Rac in neutrophils, is a member of the Rho family of GTPases that regulates the actin cytoskeleton and O2/- 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 O2/- 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 O2/- 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.
Proceedings of the National Academy of Sciences of the United States of America
Ambruso, D., Knall, C., Abell, A., & Panepinto, J. (2000). Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proceedings of the National Academy of Sciences of the United States of America, 97 (9), 4654-4659. https://doi.org/10.1073/pnas.080074897