Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency

D. A. Williams, W. Tao, F. Yang, C. Kim, Y. Gu, P. Mansfield, J. E. Levine, B. Petryniak, C. W. Derrow, C. Harris, B. Jia, Y. Zheng, D. R. Ambruso, J. B. Lowe, S. J. Atkinson, M. C. Dinauer, L. Boxer

Research output: Contribution to journalArticle

260 Citations (Scopus)

Abstract

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 (G→A at nucleotide 169) in the coding sequence was identified. This resuits 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. (C) 2000 by The American Society of Hematology.

Original languageEnglish (US)
Pages (from-to)1646-1654
Number of pages9
JournalBlood
Volume96
Issue number5
StatePublished - Sep 1 2000
Externally publishedYes

Fingerprint

rho GTP-Binding Proteins
Phagocytes
Cells
Mutation
Neutrophils
Nucleotides
Complementary DNA
cdc Genes
Monomeric GTP-Binding Proteins
Asparagine
Cell adhesion
Cell proliferation
Retroviridae
Transcription
Guanosine Triphosphate
Recombinant Proteins
Aspartic Acid
Cell Adhesion
Integrins
Superoxides

ASJC Scopus subject areas

  • Hematology

Cite this

Williams, D. A., Tao, W., Yang, F., Kim, C., Gu, Y., Mansfield, P., ... Boxer, L. (2000). Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood, 96(5), 1646-1654.

Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. / Williams, D. A.; Tao, W.; Yang, F.; Kim, C.; Gu, Y.; Mansfield, P.; Levine, J. E.; Petryniak, B.; Derrow, C. W.; Harris, C.; Jia, B.; Zheng, Y.; Ambruso, D. R.; Lowe, J. B.; Atkinson, S. J.; Dinauer, M. C.; Boxer, L.

In: Blood, Vol. 96, No. 5, 01.09.2000, p. 1646-1654.

Research output: Contribution to journalArticle

Williams, DA, Tao, W, Yang, F, Kim, C, Gu, Y, Mansfield, P, Levine, JE, Petryniak, B, Derrow, CW, Harris, C, Jia, B, Zheng, Y, Ambruso, DR, Lowe, JB, Atkinson, SJ, Dinauer, MC & Boxer, L 2000, 'Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency', Blood, vol. 96, no. 5, pp. 1646-1654.
Williams DA, Tao W, Yang F, Kim C, Gu Y, Mansfield P et al. Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood. 2000 Sep 1;96(5):1646-1654.
Williams, D. A. ; Tao, W. ; Yang, F. ; Kim, C. ; Gu, Y. ; Mansfield, P. ; Levine, J. E. ; Petryniak, B. ; Derrow, C. W. ; Harris, C. ; Jia, B. ; Zheng, Y. ; Ambruso, D. R. ; Lowe, J. B. ; Atkinson, S. J. ; Dinauer, M. C. ; Boxer, L. / Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. In: Blood. 2000 ; Vol. 96, No. 5. pp. 1646-1654.
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abstract = "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 (G→A at nucleotide 169) in the coding sequence was identified. This resuits 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. (C) 2000 by The American Society of Hematology.",
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AU - Gu, Y.

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AU - Levine, J. E.

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