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

Blood. 2000 Sep 1;96(5):1646-54.


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 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. (Blood. 2000;96:1646-1654)

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Bone Marrow Transplantation
  • Cell Movement
  • DNA Mutational Analysis
  • DNA, Complementary / chemistry
  • DNA, Complementary / genetics
  • Genes, Dominant
  • Green Fluorescent Proteins
  • Guanosine Triphosphate / metabolism
  • Hematopoiesis
  • Humans
  • Infant
  • Leukocytosis / pathology
  • Leukocytosis / therapy
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice
  • Microscopy, Fluorescence
  • Mutation
  • Neutrophils / cytology
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Phagocytes / cytology
  • Phagocytes / immunology*
  • Point Mutation
  • Protein Binding
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Retroviridae / genetics
  • Superoxides / metabolism
  • rac GTP-Binding Proteins / genetics*
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism


  • DNA, Complementary
  • Luminescent Proteins
  • Recombinant Fusion Proteins
  • Superoxides
  • Green Fluorescent Proteins
  • Guanosine Triphosphate
  • rac2 GTP-binding protein
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein