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This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Williams, D. A. Articles by Boxer, L. Search for Related Content PubMed PubMed Citation Articles by Williams, D. A. Articles by Boxer, L. Related Collections Plenary Papers Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2000, Vol. 96, No. 5, pp. 1646-1654 PLENARY PAPER Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency David A. Williams, Wen Tao, Fengchun Yang, Chaekyun Kim, Yi Gu, Pamela Mansfield, John E. Levine, Bronia Petryniak, Caroline W. Derrow, Chad Harris, Baoqing Jia, Yi Zheng, Daniel R. Ambruso, John B. Lowe, Simon J. Atkinson, Mary C. Dinauer, and Laurence Boxer From the Department of Pediatrics, Section of Pediatric Hematology/Oncology, Wells Center for Pediatric Research, and the Department of Medicine, Section of Nephrology, Howard Hughes Medical Institute, Indiana University School of Medicine, Indianapolis, IN; the Department of Biochemistry, University of Tennessee, Memphis, TN; Bonfils Blood Center and the Department of Pediatrics, University of Colorado School of Medicine, Denver, CO; the Department of Pediatrics, C. S. Mott Children's Hospital and the Department of Pathology, Howard Hughes Medical Institute, University of Michigan Medical School; Ann Arbor, MI. Rho GTPases control a variety of cellular processes, including actin polymerization, integrin complex formation, cell adhesion, gene transcription, cell cycle progression, and cell proliferation. A patient is described who has recurrent infections and defective neutrophil cellular functions similar to those found in Rac2-deficient mice. Molecular methods were used to clone the expressed Rac2 cDNA from this patient, and a single base pair change (GA at nucleotide 169) in the coding sequence was identified. This results in an asparagine for aspartic acid mutation at amino acid 57 (D57N), a residue that is involved in nucleotide binding and is conserved in all mammalian Rho GTPases. The cloned cDNA was then introduced into normal bone marrow cells through retrovirus vectors, and neutrophils expressing this mutant exhibited decreased cell movement and production of superoxide in response to fMLP. The expressed recombinant protein was also analyzed biochemically and exhibited defective binding to GTP. Functional studies demonstrated that the D57N mutant behaves in a dominant-negative fashion at the cellular level. The syndrome of Rac2 dysfunction represents a human condition associated with mutation of a Rho GTPase and is another example of human disease associated with abnormalities of small G protein signaling pathways. © 2000 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Ueyama, T. Kusakabe, S. Karasawa, T. Kawasaki, A. Shimizu, J. Son, T. L. Leto, A. Miyawaki, and N. Saito Sequential Binding of Cytosolic Phox Complex to Phagosomes through Regulated Adaptor Proteins: Evaluation Using the Novel Monomeric Kusabira-Green System and Live Imaging of Phagocytosis J. Immunol., July 1, 2008; 181(1): 629 - 640. [Abstract] [Full Text] [PDF] W. Tan, T. R. 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