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

Hsu, A. P.; Donko, A.; Arrington, M. E.; Swamydas, M.; Fink, D.; Das, A.; Escobedo, O.; Bonagura, V.; Szabolcs, P.; Steinberg, H. N.; Bergerson, J.; Skoskiewicz, A.; Makhija, M.; Davis, J.; Foruraghi, L.; Palmer, C.; Fuleihan, R. L.; Church, J. A.; Bhandoola, A.; Lionakis, M. S.; Campbell, S.; Leto, T. L.; Kuhns, D. B.; Holland, S. M.

Blood. 2019 Feb 7; 133(18):1977-1988


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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