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PNAS 97 (9): 4654-4659
Copyright © 2000 by the National Academy of Sciences.
BIOLOGICAL SCIENCES / CELL BIOLOGY |
Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation
Daniel R. Ambruso*, , ,
Cindy Knall ,
Amy N. Abell ,
Julie Panepinto¶,
Arlet Kurkchubasche¶,
Gail Thurman*,
Carolina Gonzalez-Aller*,
Andrew Hiester*,
Martin deBoer||,
Ronald J. Harbeck**,
Ryan Oyer ,
Gary L. Johnson , and
Dirk Roos||
*Bonfils Blood Center, Denver, CO 80220; Department of Pediatrics, and Pharmacology, University of Colorado Health Sciences Center, Denver, CO 80262; ¶Departments of Pediatric Hematology/Oncology and Surgery, Rhode Island Hospital, Providence, RI 02903; ||Central Laboratory of the Netherlands Blood Transfusion Service and Laboratory of Experimental and Clinical Immunology, Academic Medical Center, Amsterdam, The Netherlands; and **Clinical Labs, National Jewish Medical and Research Center, Denver, CO 80206
Accepted for publication February 22, 2000. Received for publication December 22, 1999.
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 (O2–) 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 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 (Rac2D57N). Asp57 is invariant in all defined GTP-binding proteins. Rac2D57N 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.
 To whom reprint requests should be addressed at: Bonfils Blood Center, 717 Yosemite Circle, Denver, CO 80230. E-mail: daniel.ambruso{at}UCHSC.edu.
Communicated by Henry R. Bourne, University of California, San Francisco, CA
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.080074897.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.080074897
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