Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A 2000 Apr 25;97(9):4654-9
Date
04/12/2000Pubmed ID
10758162Pubmed Central ID
PMC18288DOI
10.1073/pnas.080074897Scopus ID
2-s2.0-12944284786 (requires institutional sign-in at Scopus site) 381 CitationsAbstract
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.
Author List
Ambruso DR, Knall C, Abell AN, Panepinto J, Kurkchubasche A, Thurman G, Gonzalez-Aller C, Hiester A, deBoer M, Harbeck RJ, Oyer R, Johnson GL, Roos DMESH terms used to index this publication - Major topics in bold
Antigens, CDChemotaxis, Leukocyte
Cytosol
Guanosine 5'-O-(3-Thiotriphosphate)
Guanosine Diphosphate
Humans
Immunologic Deficiency Syndromes
Infant
Macrophage-1 Antigen
Male
NADPH Oxidases
Neutrophils
Peroxidase
Reference Values
Superoxides
rac GTP-Binding Proteins