| First Author | Hsu AP | Year | 2019 |
| Journal | Blood | Volume | 133 |
| Issue | 18 | Pages | 1977-1988 |
| PubMed ID | 30723080 | Mgi Jnum | J:276213 |
| Mgi Id | MGI:6306201 | Doi | 10.1182/blood-2018-11-886028 |
| Citation | Hsu AP, et al. (2019) Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood 133(18):1977-1988 |
| abstractText | 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. |
