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PMID: 10758162 Published · ppublish English Case Reports Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 9 ·2000-04-25 ·Pages 4654-9

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 D

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 (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.

MeSH Terms
Antigens, CD/blood Chemotaxis, Leukocyte Cytosol/metabolism Guanosine 5'-O-(3-Thiotriphosphate)/pharmacology Guanosine Diphosphate/pharmacology Humans Immunologic Deficiency Syndromes/blood,genetics,immunology Infant Macrophage-1 Antigen/blood Male NADPH Oxidases/blood,deficiency Neutrophils/physiology Peroxidase/blood Reference Values Superoxides/blood rac GTP-Binding Proteins/blood,genetics
Chemicals
Antigens, CD Macrophage-1 Antigen Superoxides Guanosine Diphosphate Guanosine 5'-O-(3-Thiotriphosphate) Peroxidase NADPH Oxidases rac2 GTP-binding protein rac GTP-Binding Proteins
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Ambruso D R
Bonfils Blood Center, Denver, CO 80220, USA. daniel.ambruso@UCHSC.edu
Knall C
Abell A N
Panepinto J
Kurkchubasche A
Thurman G
Gonzalez-Aller C
Hiester A
deBoer M
Harbeck R J
Oyer R
Johnson G L
Roos D
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.080074897
Email
daniel.ambruso@uchsc.edu
Published
2000-04-25
Pages
4654-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18288
Subset
IM
Grants
NIGMS NIH HHS · R01 GM030324 · United States
NIGMS NIH HHS · R37 GM030324 · United States
NIGMS NIH HHS · GM30324 · United States
External Links
PubMed source DOI: 10.1073/pnas.080074897 PMC Full Text View journal details
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