TY - JOUR
T1 - Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects
AU - Hsu, Amy P.
AU - Donkó, Agnes
AU - Arrington, Megan E.
AU - Swamydas, Muthulekha
AU - Fink, Danielle
AU - Das, Arundhoti
AU - Escobedo, Omar
AU - Bonagura, Vincent
AU - Szabolcs, Paul
AU - Steinberg, Harry N.
AU - Bergerson, Jenna
AU - Skoskiewicz, Amanda
AU - Makhija, Melanie Mala
AU - Davis, Joie
AU - Foruraghi, Ladan
AU - Palmer, Cindy
AU - Fuleihan, Ramsay L
AU - Church, Joseph A.
AU - Bhandoola, Avinash
AU - Lionakis, Michail S.
AU - Campbell, Sharon
AU - Leto, Thomas L.
AU - Kuhns, Douglas B.
AU - Holland, Steven M.
N1 - Funding Information:
This project was supported in part by grants from the National Institutes of Health Intramural Research Program, NIAID, and the National Cancer Institute (HHSN261200800001E and P01 CA203657) (S.L.C.).
Publisher Copyright:
Copyright 2011 by The American Society of Hematology; all rights reserved.
PY - 2019/5/2
Y1 - 2019/5/2
N2 - Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67phox, 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.
AB - Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67phox, 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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U2 - 10.1182/blood-2018-11-886028
DO - 10.1182/blood-2018-11-886028
M3 - Article
C2 - 30723080
AN - SCOPUS:85065556444
SN - 0006-4971
VL - 133
SP - 1977
EP - 1988
JO - Blood
JF - Blood
IS - 18
ER -