Editors' ChoiceImmune Cells

Rac2 Mutation May Lead to Immunodeficiency

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Science's STKE  02 May 2000:
Vol. 2000, Issue 30, pp. tw3
DOI: 10.1126/stke.2000.30.tw3

Neutrophils phagocytose foreign pathogens and kill them through an onslaught of released enzymatic granules. In addition, activated neutrophils undergo a respiratory burst that leads to the production of toxic oxygen metabolites. Ambruso et al. report the identification of a mutation in the small GTPase Rac2, the most abundant form of Rac in neutrophils, in an infant suffering from chronic severe bacterial infections and defective wound healing. A mutation from Asp57 to Asn57 in one of the patient's Rac2 genes prevents GTP loading into the mutant protein, rendering the mutant Rac2 permanently inactive. Also, the level of Rac2 protein expression in the patient's neutrophils was much lower than that observed in control neutrophils. Neutrophils from the patient were defective for chemotactic response and for the production of myeloperoxidase and reactive oxygen species. Rac2-deficient mice have been reported to have impaired neutrophil function, but still to have normal oxidase activity, suggesting that murine Rac1 protein may compensate for the absence of Rac2. Thus, the Rac2 mutant protein in the patient may exert a dominant negative effect in neutrophil signaling and activation, leading to immunodeficiency.

Ambruso, D.R., Knall, C., Abell, A.N., Panepinto, J., Kurkchubasche, A., Thurman, G., Gonzalez-Aller, C., Hiester, A., deBoer, M., Harbeck, R.J., Oyer, Johnson, G.L., and Roos, D. (2000) Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc. Natl. Acad. Sci. U.S.A. 97: 4654-4659. [Abstract] [Full Text]