Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects.
Blood
; 133(18): 1977-1988, 2019 05 02.
Article
em En
| MEDLINE
| ID: mdl-30723080
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas rac de Ligação ao GTP
/
Síndromes de Imunodeficiência
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
/
Adult
/
Animals
/
Child, preschool
/
Female
/
Humans
/
Infant
/
Newborn
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article