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 (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.
Ambruso
D R
DR
Bonfils Blood Center, Denver, CO 80220, USA. daniel.ambruso@UCHSC.edu
Knall
C
C
Abell
A N
AN
Panepinto
J
J
Kurkchubasche
A
A
Thurman
G
G
Gonzalez-Aller
C
C
Hiester
A
A
deBoer
M
M
Harbeck
R J
RJ
Oyer
R
R
Johnson
G L
GL
Roos
D
D
D015703:Antigens, CD / Q000097:blood; D002634:Chemotaxis, Leukocyte; D003600:Cytosol / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006153:Guanosine Diphosphate / Q000494:pharmacology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000097:blood* / Q000235:genetics* / Q000276:immunology; D007223:Infant; D016177:Macrophage-1 Antigen / Q000097:blood; D008297:Male; D019255:NADPH Oxidases / Q000097:blood / Q000172:deficiency; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000097:blood; D012016:Reference Values; D013481:Superoxides / Q000097:blood; D020744:rac GTP-Binding Proteins / Q000097:blood / Q000235:genetics*; D000097766:RAC2 GTP-Binding Protein
D015703:Antigens, CD; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006153:Guanosine Diphosphate; D016177:Macrophage-1 Antigen; D019255:NADPH Oxidases; D009195:Peroxidase; D013481:Superoxides; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein