Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects

  • Blood. 2019 May 2;133(18):1977-1988. doi: 10.1182/blood-2018-11-886028.
Amy P Hsu  1 ,  Agnes Donkó  2 ,  Megan E Arrington  3 ,  Muthulekha Swamydas  4 ,  Danielle Fink  5 ,  Arundhoti Das  6 ,  Omar Escobedo  2 ,  Vincent Bonagura  7 ,  Paul Szabolcs  8 ,  Harry N Steinberg  9 ,  Jenna Bergerson  1 ,  Amanda Skoskiewicz  10 ,  Melanie Makhija  10 ,  Joie Davis  1 ,  Ladan Foruraghi  1 ,  Cindy Palmer  1 ,  Ramsay L Fuleihan  10 ,  Joseph A Church  11  12 ,  Avinash Bhandoola  6 ,  Michail S Lionakis  4 ,  Sharon Campbell  13 ,  Thomas L Leto  2 ,  Douglas B Kuhns  5 ,  Steven M Holland  1
Affiliations
  • 1. Immunopathogenesis Section and.
  • 2. Molecular Defenses Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD.
  • 3. Chemistry, University of North Carolina (UNC), Chapel Hill, NC.
  • 4. Fungal Pathogenesis Section, LCIM, NIAID, NIH, Bethesda, MD.
  • 5. Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD.
  • 6. Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD.
  • 7. Cohen Children's Medical Center, New York, NY.
  • 8. UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA.
  • 9. North Shore University Hospital, New Hyde Park, NY.
  • 10. Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
  • 11. Pediatric Allergy/Immunology, Children's Hospital Los Angeles, Los Angeles, CA.
  • 12. Clinical Pediatrics, Keck School of Medicine of USC, Los Angeles, CA; and.
  • 13. Biochemistry and Biophysics, UNC Lineberger Comprehensive Cancer Center, UNC, Chapel Hill, NC.
PMID: 30723080 DOI: 10.1182/blood-2018-11-886028
Abstract

Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67 phox , activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced Actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active Guanosine triphosphate (GTP)-bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.