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.

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