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

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.

Citation

Amy P Hsu, Agnes Donkó, Megan E Arrington, Muthulekha Swamydas, Danielle Fink, Arundhoti Das, Omar Escobedo, Vincent Bonagura, Paul Szabolcs, Harry N Steinberg, Jenna Bergerson, Amanda Skoskiewicz, Melanie Makhija, Joie Davis, Ladan Foruraghi, Cindy Palmer, Ramsay L Fuleihan, Joseph A Church, Avinash Bhandoola, Michail S Lionakis, Sharon Campbell, Thomas L Leto, Douglas B Kuhns, Steven M Holland. Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood. 2019 May 02;133(18):1977-1988

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PMID: 30723080

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